Methods of treating tyrosine kinase inhibitor-induced diarrhea

Abstract

To provide a combination pharmaceutical for treating tyrosine kinase inhibitor-induced diarrhea.SOLUTION: Tyrosine kinase inhibitor-induced diarrhea is treated by administering a potassium channel inhibitor, or a CFTR chloride channel inhibitor, or a combination thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 793,291, filed January 16, 2019, which is incorporated by reference in its entirety.

[0002] Statement of Government Interest This invention was made with Government support under Grant Nos. DK072517, DK099803, DK101373, EB000415, and EY013574 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] The present invention is directed to a method of treating tyrosine kinase inhibitor-induced diarrhea by administering a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination thereof. [Background technology]

[0004] Diarrhea is a common, and sometimes treatment-limiting, side effect caused by cancer chemotherapy. Small molecule ErbB tyrosine kinase inhibitors (TKIs) are used to treat a variety of cancers that overexpress ErbB receptors, including breast cancer, non-small cell lung cancer (NSCLC), and head and neck cancer. ErbB TKI-associated diarrhea occurs in approximately 40-60% of patients, and severe (grade 3-4) diarrhea occurs in 10-20% of patients. With some ErbB TKIs, diarrhea occurs in over 90% of patients.

[0005] Current management of TKI-associated diarrhea includes fluid replacement, antimotility agents such as loperamide, and potentially TKI dose reduction or discontinuation. Given the morbidity and reduced clinical efficacy associated with severe diarrhea after TKI therapy, there remains an unmet need for effective, targeted, and safe antidiarrheal agents. Summary of the Invention

[0006] An embodiment of the present invention is directed to a method of treating a subject having tyrosine kinase inhibitor induced diarrhea, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to treat the tyrosine kinase inhibitor induced diarrhea.

[0007] Additionally, embodiments of the present invention are also directed to a method of reducing intestinal fluid secretion due to tyrosine kinase inhibitor-induced activation of potassium channels or tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium in a subject in need thereof, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to reduce said intestinal fluid secretion.

[0008] A further aspect of the present invention is directed to a method of reducing a tyrosine kinase inhibitor-induced potassium channel current or a tyrosine kinase inhibitor-induced CFTR chloride channel current in intestinal epithelium in a subject in need thereof, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor to reduce said tyrosine kinase inhibitor-induced potassium channel current or said tyrosine kinase inhibitor-induced CFTR chloride channel current.

[0009] Another aspect of the invention is directed to an improved method of treating cancer in a subject by administering to the subject a tyrosine kinase inhibitor in an amount effective to treat the cancer in the subject, the improvement comprising administering a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, in an amount effective to treat tyrosine kinase inhibitor-induced diarrhea in the subject.

[0010] Some embodiments of the present invention are directed to methods of treating cancer in a subject comprising administering to the subject a tyrosine kinase inhibitor in an amount effective to treat cancer in the subject, and a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in amounts effective to treat tyrosine kinase inhibitor-induced diarrhea in the subject.

[0011] Finally, an aspect of the present invention is directed to a method of treating diarrhea in a subject being administered a tyrosine kinase inhibitor, the method comprising determining whether the diarrhea is tyrosine kinase inhibitor induced diarrhea, and, if the diarrhea is determined to be tyrosine kinase inhibitor induced diarrhea, administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, to treat the diarrhea. [Brief description of the drawings]

[0012] [Figure 1] Figure 2 shows that tyrosine kinase inhibitors amplify carbachol-induced currents in T84 cells. (A) (Left) Short circuit currents (Isc) in T84 cells showing the response to 40 μM lapatinib, 20 μM gefitinib and 20 μM afatinib added 25 min prior to 100 μM carbachol. (Right) Summary of carbachol-induced peak currents (mean ± SEM). (B) (Left) Short circuit currents in mouse ileum showing the response to 20 μM afatinib added 25 min prior to 200 μM carbachol. (Right) Summary of peak currents (ΔIsc, mean ± SEM). (C) (Left) Short circuit currents in T84 cells showing the response to 100 ng / ml EGF and 20 μM afatinib added alone and together 25 min prior to 100 μM carbachol. (Right) Summary of peak currents (mean ± SEM). **p<0.01, ns: not significant. [Diagram 2]The kinetics and concentration dependence of afatinib amplification of the carbachol response are shown. (A) (Left) Time course of afatinib effect on carbachol-induced short-circuit current in T84 cells. Cells treated with 20 μM afatinib for different times prior to 100 μM carbachol. (Right) Summary of carbachol-induced peak currents (mean ± SEM). (B) (Left) Concentration dependence of afatinib effect. (Right) Summary of peak currents (mean ± SEM). *p<0.05, **p<0.01. Figure 3A shows the effect of BPO-27 on carbachol-induced currents in T84 cells (left) and a summary of the carbachol response as a maximal increase in short-circuit current (ΔIsc) (right). [Diagram 3] We show that afatinib-induced potentiation of carbachol currents is CFTR-dependent. (A) Short-circuit currents in T84 cells (left) showing the effects of 20 μM afatinib, 100 μM carbachol, 10 μM BPO-27 and 10 μM CFTRinh-172 with or without 30 μM BAPTA-AM as indicated. (Right) Summary of carbachol-induced peak currents (mean ± SEM), (B) Half-life (t1 / 2) of the decline phase of the carbachol response curve (mean ± SEM). **p<0.01. [Figure 4] Figure 1 shows that afatinib does not affect calcium or cAMP signaling. (A) (Left) Cytosolic Ca2+ concentration measured by Fluo-4 fluorescence. Afatinib (20 μM) is added 20 min prior to the addition of 100 μM ATP or 100 μM carbachol. (Right) Peak increase in Fluo-4 fluorescence after ATP or carbachol (mean ± SEM). (B) cAMP (mean ± SEM) in T84 cells measured 30 min after incubation with afatinib (20 μM) or forskolin (20 nM, 90 nM, 20 μM) with or without afatinib (20 μM). ns: not significant. [Diagram 5]Figure 1 shows that afatinib amplifies forskolin-induced currents in T84 cells. (A) (Left) Short-circuit currents in T84 cells in response to 20 μM afatinib (or vehicle control), followed by the indicated concentrations of forskolin, then 10 μM BPO-27. (Right) Forskolin concentration dependence of short-circuit current (mean ± SEM). (B) (Left) Short-circuit currents in T84 cells in response to 100 μM carbachol, followed by the addition of EBIO (500 μM) and / or afatinib (20 μM) added 25 min prior to 10 μM folksolin. (Right) Summary of carbachol- and forskolin-induced peak currents. p<0.05, **p<0.01. [Figure 6] Figure 2. K+ channel inhibitors block afatinib-induced potentiation of carbachol currents. (Left) Short-circuit currents in T84 cells treated with 20 μM afatinib, 30 μM clotrimazole and / or 10 μM senicapoc as indicated, 30 min before addition of 100 μM carbachol followed by 10 μM forskolin. (Right) Summary of carbachol- and forskolin-induced peak currents (mean ± SEM, *p<0.05). [Figure 7] Figure 1 shows that afatinib amplifies carbachol-induced activation of basolateral K+ conductance and apical CFTR Cl- conductance. (A) (Left) Short-circuit current in T84 cells after apical membrane permeabilization with 20 μM amphotericin B in the presence of an apical to basolateral solution K+ gradient (apical [K+] 142 mM, basolateral [K+] 5 mM). Afatinib (20 μM) and carbachol (100 μM) added as indicated. (Right) Summary of carbachol-induced peak currents (mean ± SEM). (B) (Left) Short-circuit current in T84 cells after basolateral membrane permeabilization with 250 μg / ml amphotericin B in the presence of a basolateral to apical solution Cl- gradient (basal [Cl-] 120 mM, apical [Cl-] 5 mM). Afatinib (20 μM), BPO-27 (10 μM), and carbachol (100 μM) added as indicated. (Right) Summary of carbachol-evoked peak currents (mean ± SEM). **p<0.01. [Figure 8]Figure 1 shows the involvement of ERK and PKC signaling in afatinib amplification of secretion. (A) Schematic of the proposed TKI mechanism of action. Binding of EGF to its receptor (EGFr) inhibits activation of basolateral K+ and apical Cl- channels via PKC and ERK signaling. TKIs abolish this inhibition. (B) (Left) Short-circuit currents in T84 cells showing the response to afatinib (20 μM), a PKC inhibitor (Ro31-8220, 10 μM), and an ERK inhibitor (GDC-0994, 10 μM) added alone or together 25 min prior to 100 μM carbachol. (Right) Summary of carbachol-induced peak currents (mean ± SEM, *p<0.05, **p<0.01). [Figure 9] Inhibitors of K+ and CFTR Cl- channels reduce afatinib-induced diarrhea in rats. (A) Afatinib diarrhea model in Sprague-Dawley rats orally treated with afatinib (60 mg / kg, daily). (Left) Fecal water content (percentage of moisture) measured daily. (Right) Increase in fecal water content in individual rats (fecal water for the data shown minus fecal water on day 0 for the same rat). (B) Rats were treated with afatinib starting on day 1 and with BPO-27 (10 mg / kg, twice daily, intraperitoneally) or vehicle starting on day 2. (C) Protocol as in B, except for treatment with clotrimazole (100 mg / kg, orally in two divided doses) or vehicle. (D) Protocol as in B, except for treatment with cenicapoc (30 mg / kg, orally, twice daily) or vehicle. (E) Similar protocol except for treatment with clotrimazole and BPO-27 (same doses as in B and C) or vehicle from day 1. All data reported as mean ± SEM (*p<0.05, **p<0.01) in A compared with day 0, and in B–E compared with with and without drug treatment. [Figure 10] Figure 1 shows that afatinib amplifies ATP- and thapsigargin-induced short-circuit currents in T84 cells. Responses to 20 μM afatinib added 25 min prior to 100 μM ATP (left) or 2 μM thapsigargin (right) are shown. Representative of three sets of experiments. [Figure 11] Figure 1 shows inhibition of Ca2+ and cAMP-activated K+ channels in T84 cells by clotrimazole and senicapoc. A. (Left) Short-circuit current in response to 2 μM thapsigargin (after 25 min pretreatment with 20 μM afatinib) followed by the indicated concentrations of clotrimazole or senicapoc. (Right) Inhibitory concentration dependence (mean ± SEM). (B) (Left) Short-circuit current in response to 10 μM forskolin followed by clotrimazole or senicapoc. (Right) Inhibitory concentration dependence (mean ± SEM). [Figure 12] Figure 1 shows the effect of ERK and PKC inhibitors on short circuit current in T84 cells after EGF or BAPTA-AM treatment. (A) Responses to 100 ng / ml EGF added alone or together 25 min prior to 100 μM carbachol, followed by 20 μM afatinib, 10 μM PKC inhibitor (Ro31-8220), and 10 μM ERK inhibitor (GDC-0994) are shown. (B) Short circuit currents following 30 min incubation with 30 μM BAPTA-AM, as indicated, followed by 20 μM afatinib, 10 μM PKC inhibitor, 10 μM ERK inhibitor, 10 μM BPO-27, followed by 100 μM carbachol. Representative of two sets of experiments. [Figure 13] Figure 1 shows intestinal histology of afatinib-treated rats. Sprague-Dawley rats were orally treated with afatinib (60 mg / kg) for 6 days. H&E staining shows mild damage and blunted villi in the ileum by day 4. By day 6, scattered epithelial destruction is seen in the jejunum (black arrowheads) and villous atrophy is seen in the ileum. [Figure 14] Percentage change in rat body weight during afatinib-induced diarrhea corresponds to the data in Figures 9B-E (mean ± SEM, *p<0.05). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention can be understood by reference to the following detailed description, which forms a part of this disclosure: The present invention is not limited to the specific methods, conditions, or parameters described and / or illustrated herein, and the terminology used herein is for the purpose of describing particular embodiments by way of example only, and is not intended to limit the invention as claimed.

[0014] Scientific and technical terms used in connection with this application shall have the meanings commonly understood by those of ordinary skill in the art, unless otherwise defined herein.

[0015] As used herein, the terms "composition," "compound," "drug," "pharmacologically active agent," "active agent," or "pharmaceutical product" are used interchangeably herein and refer to a compound or compounds, or a composition of matter, that upon administration to a subject (human or mammalian), elicits a desired pharmacological and / or physiological effect through local and / or systemic action.

[0016] As used herein, the term "treatment" or "therapy" (and its various forms) includes preventative (e.g., prophylactic), curative, or palliative treatment. As used herein, the term "treating" includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease, or disorder.

[0017] The term "administering" means administering a compound or composition of the invention directly, or administering a prodrug, derivative, or analog that forms an equivalent amount of the active compound or substance in the body.

[0018] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human being to whom treatment (including prophylactic treatment) with the compounds according to the invention is provided.

[0019] "Pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with human tissue without undue toxicity, irritation, allergic response, or other problem complications, commensurate with a reasonable benefit / risk ratio.

[0020] Within the scope of the present invention, the disclosed compounds can be prepared in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by making its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalic acid, isethionic acid, and the like. These pharma-ceutically acceptable salts are prepared by methods known in the art, for example, by dissolving the free amine base in aqueous alcohol with an excess of the acid, or by neutralizing the free carboxylic acid with an alkali metal base such as a hydroxide or with an amine.

[0021] The present invention is directed to a method of treating a subject having tyrosine kinase inhibitor-induced diarrhea, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to treat the tyrosine kinase inhibitor-induced diarrhea.

[0022] In some aspects, the present invention is directed to a method for treating a subject with tyrosine kinase inhibitor-induced diarrhea.As used herein, tyrosine kinase inhibitor-induced diarrhea refers to diarrhea experienced by a subject receiving tyrosine kinase chemotherapy, where the diarrhea is caused at least in part by the administration of a tyrosine kinase inhibitor.In some embodiments, the subject is receiving tyrosine kinase chemotherapy as a treatment for cancer.

[0023] According to the present invention, the subject having chemotherapy induced by tyrosine kinase inhibitor is administered with tyrosine kinase inhibitor.As used herein, tyrosine kinase inhibitor refers to a compound that inhibits tyrosine kinase.Tyrosine kinase is an enzyme that modifies proteins involved in signal transduction cascade. Exemplary tyrosine kinase inhibitors are afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, and vatalanib, and pharmaceutically acceptable salts thereof, and combinations thereof.

[0024] In some embodiments of the methods disclosed herein, the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In other embodiments, the tyrosine kinase inhibitor is afatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is axitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is bosutinib, and in some embodiments, the tyrosine kinase inhibitor is canertinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is crizotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is cabozantinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is EKB-569, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is entrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is fostamatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is gefitinib, or a pharmaceutically acceptable salt thereof.In some embodiments, the tyrosine kinase inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is imatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is leflunomide, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lenvatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is neratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is nilotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is pazopanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is semaxinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sorafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sunitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is SU6656, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Sutent, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vandetanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vatalanib, or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments of the methods disclosed herein, the subject is administered an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to treat tyrosine kinase inhibitor-induced diarrhea.

[0026] In some embodiments, the subject is administered an amount of a potassium channel inhibitor. In other embodiments, the subject is administered an amount of a CFTR chloride channel inhibitor. In yet other embodiments, the subject is administered a combination of a potassium channel inhibitor and a CFTR channel inhibitor.

[0027] As used herein, a potassium channel inhibitor refers to a compound that inhibits the passage of potassium through potassium channels, which are proteins that span cell membranes and control the flow of potassium in and out of cells.

[0028] Potassium channels contain calcium (Ca 2+ There are several types of potassium channels, including Ca-activated and cAMP-activated potassium channels, which open and close in response to the presence or absence of calcium or cAMP, respectively. In some embodiments of the methods disclosed herein, the potassium channels are 2+ In some embodiments of the methods disclosed herein, the potassium channel is a Ca-dependent potassium channel or a cAMP-dependent potassium channel. 2+ In another embodiment, the potassium channel is a cAMP-gated potassium channel.

[0029] Exemplary potassium channel inhibitors are clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, and methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate.

[0030] In some embodiments of the methods disclosed herein, the subject is administered a potassium channel inhibitor that is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

[0031] In some embodiments, the potassium channel inhibitor is clotrimazole or cenicapoc. In other embodiments, the potassium channel inhibitor is clotrimazole. In other embodiments, the potassium channel inhibitor is cenicapoc. In some embodiments, the potassium channel inhibitor is nitrendipine. In some embodiments, the potassium channel inhibitor is 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one. In some embodiments, the potassium channel inhibitor is paxillin. In some embodiments, the potassium channel inhibitor is penitrem A. In some embodiments, the potassium channel inhibitor is 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile. In some embodiments, the potassium channel inhibitor is UCL1684. In some embodiments, the potassium channel inhibitor is n-trityl-3-pyridinemethanamine. In some embodiments, the potassium channel inhibitor is methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate. Other potassium channel inhibitors are known in the art and can be used in these embodiments.

[0032] The amount of potassium channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. Amounts effective in this regard will vary depending on the characteristics and condition of the subject.

[0033] In some embodiments of the method disclosed herein, subject is administered an amount of CFTR chloride channel inhibitor.As used herein, CFTR chloride channel refers to cystic fibrosis transmembrane conductance regulator (CFTR), the cAMP-activated chloride channel expressed in the epithelium of lung, intestine, pancreas, testis and other tissues.CFTR chloride channel inhibitor is a compound that inhibits the passage of chloride through CFTR chloride channel.

[0034] Exemplary CFTR chloride channel inhibitors include (R)-BPO-27, CFTR inh -172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, and niflumic acid.

[0035] In some embodiments of the methods disclosed herein, the subject is administered (R)-BPO-27, CFTR inh -172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof.

[0036] In some embodiments, the CFTR chloride channel inhibitor is (R)-BPO-27, a compound having the following structure: [ka]

[0037] In some embodiments, the CFTR chloride channel inhibitor is inh-172. In some embodiments, the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the CFTR chloride channel inhibitor is niflumic acid.

[0038] In some embodiments, the subject is administered a pharmaceutical composition comprising a pharmaceutical excipient and an amount of a potassium channel inhibitor. In other embodiments, the subject is administered a pharmaceutical composition comprising a pharmaceutical excipient and an amount of a CFTR chloride channel inhibitor. In yet other embodiments, the subject is administered a pharmaceutical composition comprising a pharmaceutical excipient, a potassium channel inhibitor, and a CFTR channel inhibitor.

[0039] In embodiments in which a subject is administered a pharmaceutical composition comprising a CFTR chloride channel inhibitor that is (R)-BPO-27, the pharmaceutical composition may also include (S)-BPO-27. In these embodiments, the amount of (R)-BPO-27 in the pharmaceutical composition will be substantially equal to or greater than the amount of (S)-BPO-27 present in the pharmaceutical composition. For example, in some embodiments, the pharmaceutical composition may include a racemic mixture of (R / S)-BPO-27. In some aspects, the (R)-BPO-27 will be present in enantiomeric excess (ee) relative to (S)-BPO-27. For example, (R)-BPO-27 can be present in about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% ee. In some embodiments, the pharmaceutical composition will comprise (R)-BPO-27 in a % ee of greater than 99%.

[0040] The amount of CFTR chloride channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. The amount effective in this regard will vary depending on the characteristics and condition of the subject.

[0041] In some embodiments of the methods disclosed herein, the subject is administered a combination of an amount of a potassium channel inhibitor and an amount of a CFTR chloride channel inhibitor.In some embodiments in which the subject is administered a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, and the CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh -172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid.

[0042] In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc and the CFTR chloride channel inhibitor is (R)-BPO-27. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc and the CFTR chloride channel inhibitor is CFTR inh-172. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc, and the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc, and the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc, and the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc, and the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc, and the CFTR chloride channel inhibitor is niflumic acid.

[0043] In some embodiments, the present invention is directed to a method of reducing intestinal fluid secretion due to tyrosine kinase inhibitor-induced activation of potassium channels or tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium in a subject in need thereof, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to reduce said intestinal fluid secretion.

[0044] As used herein, intestinal secretion refers to the secretion of fluids from the intestinal epithelium into the intestinal lumen.

[0045] In some embodiments, intestinal fluid secretion results from tyrosine kinase inhibitor-induced activation of potassium channels in the intestinal epithelium. In some embodiments, the potassium channel is a basolateral potassium channel. A basolateral potassium channel is a potassium channel on the basolateral cell membrane (i.e., the cell membrane facing the extracellular fluid).

[0046] In some embodiments, intestinal fluid secretion results from tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium. In other embodiments, the CFTR chloride channel is an apical CFTR chloride channel in the intestinal epithelium. The apical CFTR chloride channel is a CFTR chloride channel located in the apical cell membrane (i.e., the cell membrane facing the intestinal lumen).

[0047] In some embodiments, tyrosine kinase inhibitor-induced activation of potassium channels or tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium is induced by a tyrosine kinase inhibitor, such as, for example, afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the tyrosine kinase inhibitor-induced activation of potassium channels or the tyrosine kinase inhibitor-induced activation of CFTR chloride channels in intestinal epithelium is induced by a tyrosine kinase inhibitor that is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is afatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is axitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is bosutinib, and in some embodiments, the tyrosine kinase inhibitor is canertinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is crizotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is cabozantinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is EKB-569, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is entrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is fostamatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is gefitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is imatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is leflunomide, or a pharma- ceutically acceptable salt thereof.In some embodiments, the tyrosine kinase inhibitor is lenvatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is neratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is nilotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is pazopanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is semaxinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sorafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sunitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is SU6656, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Sutent, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Vandetanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Vatalanib, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, intestinal fluid secretion is reduced by administering an effective amount of potassium channel inhibitor or an effective amount of CFTR chloride channel inhibitor to reduce said intestinal fluid secretion, or an effective amount of potassium channel inhibitor and CFTR channel inhibitor in combination.As used herein, reduced intestinal fluid secretion refers to the amount of fluid secreted into intestinal lumen compared to the amount of fluid secreted into intestinal lumen in the absence of administration of potassium channel inhibitor and / or CFTR chloride channel inhibitor.Methods for measuring reduced fluid secretion are known to those skilled in the art, and include measuring the water content of intestinal lumen contents and the amount of diarrhea discharged.

[0050] In some embodiments, intestinal fluid secretion is reduced by administering a potassium channel inhibitor that is clotrimazole, senicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc. In other embodiments, the potassium channel inhibitor is clotrimazole. In other embodiments, the potassium channel inhibitor is senicapoc. In some embodiments, the potassium channel inhibitor is nitrendipine. In some embodiments, the potassium channel inhibitor is 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one. In some embodiments, the potassium channel inhibitor is paxillin. In some embodiments, the potassium channel inhibitor is penitrem A. In some embodiments, the potassium channel inhibitor is 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile. In some embodiments, the potassium channel inhibitor is UCL1684. In some embodiments, the potassium channel inhibitor is n-trityl-3-pyridinemethanamine. In some embodiments, the potassium channel inhibitor is methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate. Other potassium channel inhibitors are known in the art and can be used in certain embodiments.

[0051] In some embodiments, intestinal fluid secretion is mediated by (R)-BPO-27, CFTR inh In some embodiments, the CFTR chloride channel inhibitor is (R)-BPO-27. In some embodiments, the CFTR chloride channel inhibitor is CFTR chloride channel inhibitor. inh -172. In some embodiments, the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the CFTR chloride channel inhibitor is niflumic acid.

[0052] In some embodiments, the present invention is directed to a method of reducing a tyrosine kinase inhibitor-induced potassium channel current or a tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium in a subject in need thereof comprising administering to the subject a potassium channel inhibitor in an amount effective to reduce said tyrosine kinase inhibitor-induced potassium channel current or a tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium, or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor.

[0053] In some embodiments, the invention is directed to a method of decreasing tyrosine kinase inhibitor-induced potassium channel currents in intestinal epithelia. In other embodiments, the invention is directed to a method of decreasing tyrosine kinase inhibitor-induced CFTR chloride channel currents in intestinal epithelia. In other embodiments, the invention is directed to a method of decreasing tyrosine kinase inhibitor-induced potassium channel currents and tyrosine kinase inhibitor-induced CFTR chloride channel currents in intestinal epithelia.

[0054] As used herein, "current" refers to the passage of ions through a channel. Thus, a potassium channel current refers to the passage of potassium ions through a potassium channel, and a CFTR chloride channel current refers to the passage of chloride ions through a CFTR chloride channel.

[0055] In some embodiments, the tyrosine kinase inhibitor-induced potassium channel current or tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium is induced by a tyrosine kinase inhibitor that is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is afatinib. In some embodiments, the tyrosine kinase inhibitor is axitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is bosutinib, and in some embodiments, the tyrosine kinase inhibitor is canertinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is crizotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is cabozantinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is EKB-569, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is entrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is fostamatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is gefitinib, or a pharmaceutically acceptable salt thereof.In some embodiments, the tyrosine kinase inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is imatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is leflunomide, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lenvatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is neratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is nilotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is pazopanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is semaxinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sorafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sunitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is SU6656, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Sutent, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vandetanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vatalanib, or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the tyrosine kinase inhibitor-induced potassium channel current in the intestinal epithelium is reduced by administering a potassium channel inhibitor, such as, for example, clotrimazole, senicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. In some embodiments, the potassium channel inhibitor is clotrimazole or senicapoc. In other embodiments, the potassium channel inhibitor is clotrimazole. In other embodiments, the potassium channel inhibitor is senicapoc. In some embodiments, the potassium channel inhibitor is nitrendipine. In some embodiments, the potassium channel inhibitor is 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one. In some embodiments, the potassium channel inhibitor is paxillin. In some embodiments, the potassium channel inhibitor is penitrem A. In some embodiments, the potassium channel inhibitor is 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile. In some embodiments, the potassium channel inhibitor is UCL1684. In some embodiments, the potassium channel inhibitor is n-trityl-3-pyridinemethanamine. In some embodiments, the potassium channel inhibitor is methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate.

[0057] In some embodiments, the tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium is (R)-BPO-27, CFTR inh In some embodiments, the CFTR chloride channel inhibitor is (R)-BPO-27. In some embodiments, the CFTR chloride channel inhibitor is CFTR chloride channel inhibitor. inh -172. In some embodiments, the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the CFTR chloride channel inhibitor is niflumic acid.

[0058] In some embodiments, the present invention is directed to a method of treating cancer in a subject, comprising administering to the subject a tyrosine kinase inhibitor in an amount effective to treat the cancer in the subject, and a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in an amount effective to treat the tyrosine kinase inhibitor-induced diarrhea in the subject.Thus, the present invention provides an improvement in such treatment, comprising administering to the subject a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in an amount effective to treat the tyrosine kinase inhibitor-induced diarrhea in the subject, in a method of treating cancer in a subject that essentially consists of administering to the subject a tyrosine kinase inhibitor in an amount effective to treat the cancer in the subject.

[0059] In some embodiments, the cancer is adenoid cystic carcinoma, adrenal gland tumor, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, male breast cancer, carcinomatous tumor, cervical cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor-GIST, HER2 positive breast cancer, renal cancer, laryngeal cancer, leukemia, liver cancer, lobular carcinoma, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant glioma. , melanoma, meningioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, nasopharyngeal carcinoma, neuroendocrine tumors, neurobasal cell carcinoma syndrome, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, pituitary cancer, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, skin cancer (non-melanoma), small intestine cancer, stomach cancer, testicular cancer, thyroid cancer, uterine (endometrial) cancer, or vaginal cancer.

[0060] In some embodiments, the cancer is gastrointestinal stromal tumor, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, non-small cell lung cancer, hepatocellular carcinoma, pancreatic cancer, renal cancer, breast cancer, colorectal cancer, ovarian cancer, melanoma, prostate cancer, squamous cell carcinoma, or renal cancer.

[0061] In some embodiments, the subject has a mutation in a gene encoding an ErbB family member. The ErbB gene can encode epidermal growth factor receptor (EGFR). In some embodiments, the EGFR comprises a mutation in exon 18 (Kobayashi et al. Clin. Cancer Res. 21:5305-5313, 2015, incorporated herein by reference in its entirety). In certain embodiments, the mutation is in a codon encoding an amino acid at position E709, G719, or a combination thereof. For example, the mutation can be in a codon encoding E709K, E709A, E709G, E709V, E709H, G719A, G719S, G719C, G719D, G719V, or a combination thereof. In certain embodiments, the mutation is a deletion of exon 18. For example, the deletion of exon 18 can be DelE709_T710insD.

[0062] In some embodiments of the methods disclosed herein, the subject is administered an amount of a tyrosine kinase inhibitor effective to treat the subject's cancer. The amount of the tyrosine kinase inhibitor effective in this regard will vary depending on the tyrosine kinase inhibitor and the characteristics and condition of the subject.

[0063] In some embodiments of the methods of treating cancer, the tyrosine kinase inhibitor administered to the subject is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating cancer, the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments of the method of treating cancer, the tyrosine kinase inhibitor is afatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is axitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is bosutinib, and in some embodiments, the tyrosine kinase inhibitor is canertinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is crizotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is cabozantinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is EKB-569, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is dasatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is entrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is erlotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is fostamatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is gefitinib, or a pharmaceutically acceptable salt thereof.In some embodiments, the tyrosine kinase inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is imatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is leflunomide, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is lenvatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is neratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is nilotinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is pazopanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is semaxinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sorafenib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is sunitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is SU6656, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is Sutent, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vandetanib, or a pharmaceutically acceptable salt thereof. In some embodiments, the tyrosine kinase inhibitor is vatalanib, or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments of the methods of treating cancer, the subject is administered a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in an amount effective to treat the subject's tyrosine kinase inhibitor-induced diarrhea.

[0065] In some embodiments, the subject is administered a potassium channel inhibitor, such as, for example, clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. In some embodiments, the potassium channel inhibitor is clotrimazole or cenicapoc. In other embodiments, the potassium channel inhibitor is clotrimazole. In other embodiments, the potassium channel inhibitor is cenicapoc. In some aspects, the potassium channel inhibitor is nitrendipine. In some embodiments, the potassium channel inhibitor is 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one. In some embodiments, the potassium channel inhibitor is paxillin. In some embodiments, the potassium channel inhibitor is penitrem A. In some embodiments, the potassium channel inhibitor is 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile. In some embodiments, the potassium channel inhibitor is UCL1684. In some embodiments, the potassium channel inhibitor is n-trityl-3-pyridinemethanamine. In some embodiments, the potassium channel inhibitor is methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate.

[0066] The amount of potassium channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. Amounts effective in this regard will vary depending on the characteristics and condition of the subject.

[0067] In some embodiments, the subject is receiving, e.g., (R)-BPO-27, CFTR inh In some embodiments, the CFTR chloride channel inhibitor is administered, such as CFTR chloride channel inhibitors such as CFTR chloride channel inhibitors (R)-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or combinations thereof. In some embodiments, the CFTR chloride channel inhibitor is (R)-BPO-27. In some embodiments, the CFTR chloride channel inhibitor is CFTR chloride channel inhibitors (R)-BPO-27. inh -172. In some embodiments, the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the CFTR chloride channel inhibitor is niflumic acid.

[0068] The amount of CFTR chloride channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. The amount effective in this regard will vary depending on the characteristics and condition of the subject.

[0069] In some embodiments, the subject is administered the combination of potassium channel inhibitor and CFTR chloride channel inhibitor.The combination of potassium channel inhibitor and CFTR chloride channel inhibitor is effective for treating tyrosine kinase inhibitor-induced diarrhea.The effective amount in this respect will vary according to the characteristics and condition of the subject.

[0070] In some embodiments, the present invention is directed to a method of treating diarrhea in a subject being administered a tyrosine kinase inhibitor, the method comprising: (1) determining whether the diarrhea is tyrosine kinase inhibitor-induced diarrhea; and (2) if the diarrhea is determined to be tyrosine kinase inhibitor-induced diarrhea, administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, to treat the diarrhea.

[0071] In this embodiment, the method includes determining whether the diarrhea is tyrosine kinase inhibitor-induced diarrhea. Methods for determining whether the diarrhea is tyrosine kinase inhibitor-induced diarrhea are known to those skilled in the art and include, for example, assessing whether the subject is undergoing tyrosine kinase inhibitor therapy, such as by questioning the subject. In other embodiments, the assessment requires assessing the subject's medical history, assessing the subject's diet, and assessing whether the subject has developed a bacterial or viral infection. The method for determining whether the diarrhea is tyrosine kinase inhibitor-induced also includes excluding any other causes of diarrhea.

[0072] In the method of this embodiment, once the subject's diarrhea is determined to be tyrosine kinase inhibitor-induced diarrhea, the subject is administered an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor to treat the diarrhea.

[0073] In some embodiments of this aspect, the subject is administered a potassium channel inhibitor, such as, for example, clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. In some embodiments, the potassium channel inhibitor is clotrimazole or cenicapoc. In other embodiments, the potassium channel inhibitor is clotrimazole. In other embodiments, the potassium channel inhibitor is cenicapoc. In some embodiments, the potassium channel inhibitor is nitrendipine. In some embodiments, the potassium channel inhibitor is 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one. In some embodiments, the potassium channel inhibitor is paxillin. In some embodiments, the potassium channel inhibitor is penitrem A. In some embodiments, the potassium channel inhibitor is 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile. In some embodiments, the potassium channel inhibitor is UCL1684. In some embodiments, the potassium channel inhibitor is n-trityl-3-pyridinemethanamine. In some embodiments, the potassium channel inhibitor is methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate.

[0074] The amount of potassium channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. Amounts effective in this regard will vary depending on the characteristics and condition of the subject.

[0075] In other embodiments of this aspect, the subject is administered a CFTR inh In some embodiments, the CFTR chloride channel inhibitor is administered, such as CFTR chloride channel inhibitors such as CFTR chloride channel inhibitors (R)-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or combinations thereof. In some embodiments, the CFTR chloride channel inhibitor is (R)-BPO-27. In some embodiments, the CFTR chloride channel inhibitor is CFTR chloride channel inhibitors (R)-BPO-27. inh -172. In some embodiments, the CFTR chloride channel inhibitor is GlyH-101. In some embodiments, the CFTR chloride channel inhibitor is glibenclamide. In some embodiments, the CFTR chloride channel inhibitor is diphenylamine-2-carboxylate. In some embodiments, the CFTR chloride channel inhibitor is 5-nitro-2-(3-phenylpropylamino)benzoate. In some embodiments, the CFTR chloride channel inhibitor is niflumic acid.

[0076] The amount of CFTR chloride channel inhibitor administered is an amount effective to treat tyrosine kinase inhibitor-induced diarrhea. The amount effective in this regard will vary depending on the characteristics and condition of the subject.

[0077] In some embodiments of this aspect, the subject is administered an amount of or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor effective to treat tyrosine kinase inhibitor-induced diarrhea. The amount effective in this regard will vary depending on the characteristics and condition of the subject. EXAMPLES

[0078] The following examples are provided to better understand the subject matter described herein.These examples should not be considered as limiting the subject matter described herein.It is understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in view thereof are obvious to those skilled in the art, and are included in the scope of the present invention and can be made without departing from the scope of the present invention. Abbreviation BAPTA-1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid EGF-epidermal growth factor ERK-Extracellular signal-regulated kinase PKC - Protein Kinase C

[0079] Chemicals Lapatinib and gefitinib are purchased from Synkinase (San Diego, CA), and afatinib is purchased from Abcam (Cambridge, MA). BAPTA-AM is purchased from EMD Millipore (Billerica, MA). Clotrimazole is purchased from Spectrum Chemicals (Gardena, CA), and senicapoq is purchased from MedChem Express (Monmouth, NJ). PKC inhibitor Ro31-8220 is purchased from TOCRIS Bioscience (Bristol, UK), and ERK inhibitor GDC-0994 is purchased from APExBIO (Boston, MA). EGF and thapsigargin are purchased from Abcam (Cambridge, MA). Forskolin, carbachol, and other chemicals are purchased from Sigma-Aldrich (St. Louis, MO).CFTRinh-172 and (R)-BPO-27 (herein referred to as BPO-27) have been reported in Snyder DS, Tradtrantip L, Yao C, Kurth MJ, and Verkman AS. Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem. 2011;54(15):5468-77, Snyder DS, Tradtrantip L, Battula S, Yao C, Phuan PW, Fettinger JC, et al. Absolute composition and biological properties of enantiomers of CFTR inhibitor BPO-27. ACS Med Chem Lett. 2013;4(5):456-9, Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, et al. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest. 2002;110(11):1651-8.

[0080] cell culture T84 cells (ATCC CCL-248) are cultured in a 1:1 mixture of DMEM / Ham's F-12 medium supplemented with 10% FBS, 100 U / mL penicillin, and 100 µg / mL streptomycin. Cells are grown on Snapwell inserts (Costar Corning, Horseheads, NY) at 37 °C in 5% CO2 / 95% air and used 7-10 days after seeding.

[0081] Short circuit current measurement T84 cells are mounted in an Ussing chamber and bathed in symmetric HCO3 buffer (pH 7.4) containing (in mM) 120 NaCl, 5 KCl, 1 MgCl2, 1 CaCl2, 10 D-glucose, 5 HEPES, and 25 NaHCO3. The solution is aerated with 95% O2 / 5% CO2 and maintained at 37°C. Basolateral K + as the main charge carrying ion to measure conductance K+ A solution containing K was used to transfer the K from the mucosa to the serosa. + A gradient is established. The apical solution contained (in mM): 142.5 K-gluconate, 1.25 CaCl2, 0.40 MgSO4, 0.43 KH2PO4, 0.35 Na2HPO4, 10 HEPES, 5.6 D-glucose (pH 7.4). In the basolateral solution, 142.5 mM K-gluconate is replaced with 5.4 mM K-gluconate and 136.9 mM N-methylglucamine, and the apical membrane is permeabilized with 20 μM amphotericin B (Rufo PA, Merlin D, Riegler M, Ferguson-Maltzman MH, Dickinson BL, Brugnara C, et al. The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human intestinal T84 cells via blockade of distinct basolateral K + conductances.Demonstration of efficacy in intact rabbit colon and in an in vivo mouse model of cholera.J Clin Invest.1997;100(12):3111-20). Apical Cl - For conductance measurements, basolateral to apical Cl -Apply the gradient. The basolateral solution contained the following (in mM): 120 NaCl, 1 MgCl2, 1 CaCl2, 10 D-glucose, 5 HEPES, and 25 NaHCO3 (pH 7.4). In the apical solution, 120 mM NaCl is replaced with 5 mM NaCl and 115 mM sodium gluconate, and the basolateral membrane is permeabilized with 250 μg / mL amphotericin B (Pongkorpsakol P, Pathomthongtaweechai N, Srimanote P, Soodvilai S, Chatsudthipong V, and Muanprasat C. Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera. PLoS Negl Trop Dis. 2014;8(9):e3119). Short circuit currents are measured using an EVC4000 multichannel voltage clamp (World Precision Instruments, Sarasota, FL). For intestinal short circuit current measurements, CD1 mice are anesthetized with isoflurane. The ileum is removed, washed with ice-cold Krebs buffer, opened along the mesenteric border, and the full thickness layer is mounted in a micro-Ussing chamber (area 0.7 cm2, World Precision Instruments, Sarasota, FL). The hemi-chamber is filled with oxygenated Krebs-bicarbonate solution.

[0082] Intracellular calcium and cAMP measurements T84 cells are seeded in 96-well black-walled microplates. Confluent cells are loaded with Fluo-4 NW (Invitrogen, Carlsbad, CA) 72 h after seeding. In some studies, cells are pretreated with afatinib for 30 min. Fluo-4 fluorescence is measured at excitation / emission wavelengths of 495 / 516 nm using a Tecan Infinite M1000 plate reader (Tecan Groups Ltd, Männedorf, Switzerland). For cAMP assays, T84 cells are grown in 24-well plates, treated with afatinib and / or forskolin for 30 min, lysed by repeated freeze / thawing, centrifuged to remove cell debris, and supernatants are assayed for cAMP using a parameter cAMP immunoassay kit (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions.

[0083] statistics Data are expressed as mean ± SEM. Statistical analysis is performed using the Prism 5 GraphPad software package (San Diego, CA). Statistical comparisons are made using Student's test or ANOVA. A value of p<0.05 is considered statistically significant.

[0084] ErbB tyrosine kinase inhibitors amplify carbachol-induced currents in enterocytes. The ErbB TKIs lapatinib, gefitinib, and afatinib inhibit Cl in T84 human colonic epithelial cells. - The effect on secretory responses is examined. Short-circuit current is measured in T84 cell monolayers with the same solution bathing the apical and basolateral surfaces. Figure 1A shows that administration of an ErbB TKI alone does not increase short-circuit current, indicating that the ErbB TKI inhibits apical membrane Cl receptors such as CFTR or CaCCs. - Channel or basolateral K +These results suggest that ErbB TKIs do not directly activate other transporters involved in the generation of secretory currents, such as the Cl channel. However, addition of ErbB TKIs prior to the muscarinic agonist carbachol significantly inhibited subsequent Cl - ErbB TKIs also amplify the secretory response by 2-3 fold. 2+ Cl-ATPase inhibitor thapsigargin induces - also increased, indicating that the effects of TKIs are not specific to cholinergic agonists.

[0085] FIG. 1B shows that, similar to T84 cells, afatinib by itself does not increase short-circuit current in mouse ileum, but it does amplify the current response to carbachol.

[0086] To test whether the effect of afatinib involves EGF signaling, we measured short-circuit currents in cells pretreated with EGF alone, afatinib alone, and EGF and afatinib (Fig. 1C). - Afatinib overcomes EGF-mediated inhibition of carbachol-induced currents, and similar current responses are seen in cells pretreated with afatinib alone and EGF + afatinib. Blockade of EGF inhibition of carbachol-induced currents by afatinib significantly reduces Cl - These results suggest that the amplification of the secretory response occurs via inhibition of ErbB receptor activation.

[0087] Kinetics and concentration dependence of afatinib-induced amplification of the carbachol response in T84 cells. Figure 2A shows the amplifying effect of afatinib on carbachol-induced short-circuit currents, which increases with time between afatinib and carbachol addition, with a half-maximal effect seen at 10-15 min and a maximal effect at approximately 25 min. When added 25 min prior to carbachol, the effect of afatinib is concentration dependent, with an EC50 of approximately 5 µM (Figure 2B).

[0088] Carbachol-induced Cl- Afatinib-mediated amplification of secretion is CFTR dependent Carbachol increases intracellular Ca 2+ Cl through activation of signal transduction and apical membrane CaCC activation - Afatinib-induced amplification of the carbachol response to induce Ca secretion 2+ We investigated whether CFTR-selective inhibitor BPO-27 is involved in the increase in intracellular Ca and CaCC activation. Figure 3A (left) shows that the CFTR-selective inhibitor BPO-27 has little effect on the carbachol-induced current in T84 cells. However, BPO-27 blocks the afatinib enhancement of the carbachol-induced current. 2+ Treatment with BAPTA-AM to block the increase in CFTR largely prevents the carbachol response. However, in BAPTA-treated cells, afatinib produces a substantial residual carbachol response, which is comparable to the two chemically unrelated CFTR inhibitors BPO-27 and CFTR inh -172. The carbachol response curve is broader (slower return to baseline) in the presence of afatinib versus its absence.

[0089] Figure 3A (right) shows the carbachol response as a maximal increase in short-circuit current (ΔIsc). - Afatinib-induced enhancement of Ca secretion is CFTR-dependent 2+ The amplified current was blocked by a CFTR inhibitor but not by BAPTA treatment, suggesting that t 1 / 2 In terms of curve shape quantified by analysis, Ca 2+ These responses have distinct properties from the dependent carbachol response (Fig. 3B ).

[0090] Afatinib has no effect on calcium or cAMP signaling Residual afatinib-amplified carbachol currents in BAPTA-treated cells and their suppression by CFTR inhibitors indicate that afatinib effects on intracellular Ca 2+These results suggest that afatinib is not mediated by cAMP signaling and may possibly be involved in cAMP signaling. Consistent with this, as shown in Figure 4A, afatinib by itself does not increase cytoplasmic Ca 2+ Ca concentration after ATP or carbachol was not increased. 2+ Furthermore, as shown in Figure 4B, afatinib itself does not increase total cellular cAMP or affect the increase in cAMP following forskolin.

[0091] Afatinib inhibits the basolateral K+ channel and the apical CFTR Cl - Amplifying carbachol-induced activation of the channel Although afatinib does not affect cAMP levels, we investigate the possibility that afatinib affects the short-circuit current induced by forskolin (cAMP). Afatinib amplifies the forskolin-induced current response, as shown in Figure 5A, although to a lesser extent than that seen with carbachol. This result is consistent with the increase in intracellular Ca 2+ The lack of effect of afatinib on cAMP and Cl, together with the finding that afatinib itself does not elicit a current response. - Afatinib amplification of the secretory response is partially due to basolateral membrane K + These results suggest that activation of the epithelial Ca channel(s) may be involved. Afatinib responses were associated with increased Ca 2+ activation K + Channel and cAMP-activated K + Increase the conductance of both K channels + This is mimicked by the channel agonist EBIO. Figure 5B shows that EBIO pretreatment amplifies the carbachol and forskolin current responses. Pretreatment with EBIO and afatinib showed a similar effect to pretreatment with EBIO alone.

[0092] Clotrimazole, an FDA-approved antifungal drug, inhibits intermediate conductance Ca 2+ activation K +Channel (Kca3.1) and epithelial cAMP-activated K + A well-characterized inhibitor of the channel, the chemically related investigational drug senicapoc, is an inhibitor of Kca3.1. In T84 cells, as shown in Figure 6, clotrimazole or senicapoc significantly prevented carbachol- and forskolin-induced current responses with or without afatinib pretreatment. The small residual currents are due to the presence of other K channels rather than incomplete inhibition by clotrimazole or senicapoc. + This may be due to the presence of Ca channels, since higher concentrations of these compounds do not inhibit the residual current (data not shown). In patch clamp studies, clotrimazole inhibited epithelial Ca 2+ activation K + It has been reported that clotrimazole and cenicapoc completely inhibit the Ca channel. 2+ dependent basolateral K + Conductance and cAMP-dependent basolateral K + Low micromolar IC for inhibition of conductance 50 This shows that.

[0093] basolateral membrane K + To measure the conductance directly, Cl - and Na + Amphotericin B and apical to basolateral K in solution free of amphotericin B + Short-circuit currents are measured in T84 cells after permeabilization of the apical membrane with a gradient (Figure 7A). Pretreatment with afatinib increased the carbachol response by approximately two-fold, which was largely blocked by clotrimazole. Thus, afatinib inhibits the basolateral membrane in response to carbachol in T84 cells. K+ Amplify the opening of the channel.

[0094] basolateral K + In addition to afatinib's effect of amplifying channel activation, the data in Figure 2 also show that afatinib also amplifies apical CFTR Cl -The short-circuit current is the current that amplifies the Cl channel activation from the basolateral to the apical side after permeabilization of the basolateral membrane. - The carbachol response is measured by the gradient (Figure 7B). Pretreatment with afatinib increases the carbachol response by more than four-fold, which is blocked by BPO-27. Thus, the afatinib-amplified carbachol response also involves increased activation of the apical membrane CFTR Cl- channel.

[0095] Afatinib-induced diarrhea in rats was +チャネル and CFTR Cl - Decreased by channel inhibition Afatinib-induced diarrhea in rats Female Sprague-Dawley rats (8–10 weeks old) were administered oral afatinib (60 mg / kg po) daily for 6 days. BPO-27 (10 mg / kg, i.p.), clotrimazole (100 mg / kg, po) or senicapoq (30 mg / kg, po), or (R)-BPO-27 + clotrimazole were administered twice daily to afatinib-treated rats. (R)-BPO-27 and senicapoq are dissolved in saline containing 5% DMSO and 10% Kolliphor HS. Clotrimazole is dispersed in peanut oil and sonicated for 30 min. Rats were placed individually in metabolic cages and given access to water and food. Fecal samples are collected for 5 h. To measure fecal water content, fecal samples are dried at 70 °C for 24 h and water content is calculated as (wet weight - dry weight) / wet weight.

[0096] Following initial dose-finding studies in mice and rats with several TKIs, using fecal water content (from wet and dry weight measurements) as an endpoint, we establish a robust, short-term experimental animal model of afatinib diarrhea involving daily oral administration of 60 mg / kg afatinib to rats. By days 4–5, fecal water content, as determined by the ratio of fecal wet to dry weight, increased to >80%, exceeding approximately 60% of baseline (Figure 9A). Examination of intestinal histology showed relatively minor pathology until day 4, but greater epithelial destruction thereafter. We then used the 5-day afatinib model to evaluate the efficacy and safety of K + The potential antidiarrheal effects of the channel blockers clotrimazole and cenicapoc, and the CFTR inhibitor BPO-27 will be tested.

[0097] Intraperitoneal administration of 10 mg / kg BPO-27 twice daily to rats, starting 1 day after the first afatinib dose, significantly reduced the afatinib-induced increase in fecal water content (Figure 9B). BPO administration was chosen based on previous pharmacokinetic data in mice (Cil O, Phuan PW, Gillespie AM, Lee S, Tradtrantip L, Yin J, et al. Benzopyrimido-pyrrolo-oxazine-dione CFTR inhibitor(R)-BPO-27 for antisecretory therapy of diarrheas caused by bacterial enterotoxins. FASEB J. 2017;31(2):751-60), and preliminary studies in rats to generate predicted therapeutic concentrations in serum. The increase in fecal water content is inhibited by approximately 50% on days 3 and 4. The decline in inhibitor effect by day 5 may be related to afatinib-induced epithelial damage and an increase in the nonsecretory component of diarrhea in this model.

[0098] Oral treatment of rats with 100 mg / kg clotrimazole (administered orally in two divided doses), based on published data (Takei S, Iseda T, and Yokoyama M. Inhibitory effect of clotrimazole on angiogenesis associated with bladder epithelium proliferation in rats. Int J Urol. 2003;10(2):78-85; Khalid MH, Tokunaga Y, Caputy AJ, and Walters E. Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole. J Neurosurg. 2005;103(1):79-86; Rufo PA, Merlin D, Riegler M, Ferguson-Maltzman MH, Dickinson BL, Brugnara C, et al. The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human intestinal T84 cells via blockade of distinct basolateral K +The dose and administration regimen selected from afatinib-treated rats (Table 3) also significantly reduced the increase in fecal water content in afatinib-treated rats, inhibiting it by approximately 75% on days 3 and 4 (Figure 9D). A significant but smaller reduction in fecal water content increase is seen with senicapoc at 30 mg / kg twice daily, a dose selected from published data (Staal RGW, Khayrullina T, Zhang H, Davis S, Fallon SM, Cajina M, et al. Inhibition of the potassium channel KCa3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury. Eur J Pharmacol. 2017;795:1-7; Paka L, Smith DE, Jung D, McCormack S, Zhou P, Duan B, et al. Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease. World J Gastroenterol. 2017;23(23):4181-90).

[0099] Without being bound by theory, the data herein suggest that ErbB TKIs typically inhibit basolateral K + and apical Cl - By preventing EGF-mediated ERK activity, which acts to limit both Cl channel activity and - Thus, loss of ERK-mediated inhibition amplifies channel activity and leads to excessive fluid secretion. Our data suggest that K + Channels and CFTR Cl at the apical membrane- Supporting a pro-secretory mechanism of ErbB TKI diarrhea involving amplification of channel activity.

[0100] The present disclosure is also directed to the following aspects: Embodiment 1. A method of treating a subject having tyrosine kinase inhibitor induced diarrhea, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, to treat the tyrosine kinase inhibitor induced diarrhea. Embodiment 2. The method of embodiment 1, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 3. The method of embodiment 2, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 4. The method of embodiment 3, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. 5. Potassium channels are Ca 2+ The method of any one of the preceding aspects, wherein the activated potassium channel. Embodiment 6. The method of any one of the preceding embodiments, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 7. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh The method of any one of the preceding aspects, wherein the active ingredient is -172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof. Embodiment 8. The method of any one of the preceding embodiments, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. Embodiment 9. A method of reducing intestinal fluid secretion due to tyrosine kinase inhibitor-induced activation of potassium channels or tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium in a subject in need thereof, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to reduce said intestinal fluid secretion. Embodiment 10. The method of embodiment 9, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 11. The method of embodiment 10, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 12. The method of embodiment 11, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. Embodiment 13. The method of any one of embodiments 9 to 12, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 14. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh 14. The method of any one of aspects 9 to 13, wherein the active ingredient is benzoyl peroxidase-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof. Embodiment 15 The method of embodiment 14, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. Embodiment 16. A method of reducing a tyrosine kinase inhibitor-induced potassium channel current or a tyrosine kinase inhibitor-induced CFTR chloride channel current in an intestinal epithelium in a subject in need thereof, comprising administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, to reduce said tyrosine kinase inhibitor-induced potassium channel current or said tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium. Embodiment 17. The method of embodiment 16, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 18. The method of embodiment 17, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 19. The method of embodiment 18, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. Embodiment 20. The method of any one of embodiments 16 to 19, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 21. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh 21. The method of any one of aspects 16 to 20, wherein the active ingredient is benzoyl peroxidase-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof. Embodiment 22 The method of embodiment 21, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. Embodiment 23. An improved method of treating cancer in a subject consisting essentially of administering to the subject a tyrosine kinase inhibitor in an amount effective to treat the cancer in the subject, the improvement comprising administering a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in an amount effective to treat tyrosine kinase inhibitor-induced diarrhea in the subject. Embodiment 24. The improvement according to embodiment 23, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 25. The improvement according to embodiment 24, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 26 The improvement according to embodiment 25, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. Embodiment 27. The improvement of any one of embodiments 23 to 26, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 28. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh 28. The improvement according to any one of aspects 23 to 27, wherein the active ingredient is selected from the group consisting of benzodiazepine, benzoyl pertazolidine ... Embodiment 29. The improvement according to embodiment 28, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. 30. A method of treating diarrhea in a subject receiving a tyrosine kinase inhibitor, comprising: determining whether the diarrhea is tyrosine kinase inhibitor-induced diarrhea; If the diarrhea is determined to be tyrosine kinase inhibitor-induced diarrhea, administering to the subject an effective amount of a potassium channel inhibitor or an effective amount of a CFTR chloride channel inhibitor, or an effective amount of a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, to treat the diarrhea. Aspect 31. The method of aspect 30, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 32. The method of embodiment 31, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 33 The method of embodiment 32, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. Embodiment 34. The method of any one of embodiments 30 to 33, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 35. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh 35. The method of any one of aspects 30 to 34, wherein the active ingredient is benzoyl peroxidase-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof. Embodiment 36 The method of embodiment 35, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. Embodiment 37. A method of treating cancer in a subject, comprising administering to the subject a tyrosine kinase inhibitor in an amount effective to treat cancer in the subject, and a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, in amounts effective to treat tyrosine kinase inhibitor-induced diarrhea in the subject. Embodiment 38. The method of embodiment 37, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 39. The method of embodiment 38, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof. Embodiment 40 The method of embodiment 39, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof. Embodiment 41. The method of any one of embodiments 37 to 40, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof. 42. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR inh 42. The method of any one of aspects 37-41, wherein the active ingredient is benzoyl peroxidase-172, GlyH-101, glibenclamide, diphenylamine-2-carboxylate, 5-nitro-2-(3-phenylpropylamino)benzoate, or niflumic acid, or a combination thereof. Embodiment 43 The method of embodiment 42, wherein the CFTR chloride channel inhibitor is (R)-BPO-27. Aspect 44. The cancer is selected from the group consisting of adenoid cystic carcinoma, adrenal gland tumor, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, male breast cancer, carcinomatous tumor, cervical cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor-GIST, HER2 positive breast cancer, kidney cancer, laryngeal cancer, leukemia, liver cancer, lobular carcinoma, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant glioma, melanoma, meningioma, multiple endocrine tumors, 44. The method of any one of aspects 37 to 43, wherein the cancer is tumor type 1, multiple endocrine neoplasia type 2, multiple myeloma, nasopharyngeal carcinoma, neuroendocrine tumors, neurobasal cell carcinoma syndrome, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, parathyroid cancer, penile cancer, peritoneal cancer, pituitary cancer, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, skin cancer (non-melanoma), small intestine cancer, gastric cancer, testicular cancer, thyroid cancer, uterine (endometrial) cancer, or vaginal cancer. Embodiment 45. The method of embodiment 44, wherein the cancer is breast cancer, HER2-positive breast cancer, non-small cell lung cancer (NSCLC), or head and neck cancer. Embodiment 46. The method according to any one of embodiments 37 to 45, wherein the tyrosine kinase inhibitor is administered simultaneously with a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor. Embodiment 47. The method according to any one of embodiments 37 to 45, wherein the tyrosine kinase inhibitor is administered prior to the potassium channel inhibitor or the CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor. Embodiment 48. The method according to any one of embodiments 37 to 45, wherein the tyrosine kinase inhibitor is administered after the potassium channel inhibitor or the CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor. Embodiment 49 The method according to any one of embodiments 37 to 48, wherein the subject has a mutation in a gene encoding an ErbB family member. Embodiment 50 The method according to embodiment 49, wherein the ErbB gene is epidermal growth factor receptor (EGFR). Embodiment 51. The method of embodiment 50, wherein the mutation is in exon 18. Embodiment 52. The method according to embodiment 50 or 51, wherein the mutation is in a codon encoding an amino acid at position E709, G719, or a combination thereof. Embodiment 53. The method of embodiment 52, wherein the mutation encodes E709K, E709A, E709G, E709V, E709H, G719A, G719S, G719C, G719D, G719V, or a combination thereof. Embodiment 54. The method according to embodiment 50 or 51, wherein the mutation comprises a deletion of exon 18. Embodiment 55. The method according to embodiment 54, wherein the exon 18 deletion is DelE709_T710insD. Embodiment 56. The method of any one of embodiments 7, 8, 14, 15, 21, 22, 28, 29, 35, 36, 42, 43, or 44-55, wherein the (R)-BPO-27 is administered as a racemic mixture with (S)-BPO-27.

Claims

1. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, for use in a method of treating a subject having tyrosine kinase inhibitor-induced diarrhea.

2. 2. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 1, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

3. 3. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 2, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

4. 4. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 3, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

5. The potassium channel is Ca ２＋ A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 1 to 4, which is an activated potassium channel.

6. 6. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 1 to 5, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

7. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 7. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 1 to 6, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

8. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 1 to 7, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

9. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, for use in a method for reducing intestinal fluid secretion due to tyrosine kinase inhibitor-induced activation of potassium channels or tyrosine kinase inhibitor-induced activation of CFTR chloride channels in the intestinal epithelium in a subject in need thereof.

10. 10. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR channel inhibitor, of claim 9, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

11. 11. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR channel inhibitor, of claim 10, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

12. 12. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to claim 11, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

13. 13. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to any one of claims 9 to 12, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

14. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 14. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to any one of claims 9 to 13, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

15. 15. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to claim 14, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

16. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, for use in a method for reducing a tyrosine kinase inhibitor-induced potassium channel current or a tyrosine kinase inhibitor-induced CFTR chloride channel current in the intestinal epithelium in a subject in need thereof.

17. 17. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR channel inhibitor, of claim 16, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

18. 18. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to claim 17, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

19. 19. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to claim 18, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

20. 20. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to any one of claims 16 to 19, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

21. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 21. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to any one of claims 16 to 20, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

22. 22. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, according to claim 21, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

23. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, for use in a method of treating cancer in a subject, comprising administering to the subject a tyrosine kinase inhibitor in an amount effective to treat the cancer in the subject.

24. 24. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 23, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

25. 25. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 24, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

26. 26. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 25, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

27. 27. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of any one of claims 23 to 26, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

28. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 28. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 23 to 27, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

29. 29. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 28, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

30. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, for use in a method for treating diarrhea in a subject receiving a tyrosine kinase inhibitor, the method comprising determining whether the diarrhea is tyrosine kinase inhibitor-induced diarrhea.

31. 31. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 30, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

32. 32. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 31 , wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

33. 33. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 32, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

34. 34. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of any one of claims 30 to 33, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

35. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 35. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 30 to 34, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

36. 36. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 35, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

37. A potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, for use in a method for treating cancer in a subject, said method comprising administering to the subject a tyrosine kinase inhibitor in an amount effective to treat cancer in the subject.

38. 38. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 37, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vatalanib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

39. 39. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 38, wherein the tyrosine kinase inhibitor is afatinib, canertinib, cetuximab, erlotinib, gefitinib, or lapatinib, or a pharma- ceutically acceptable salt thereof, or a combination thereof.

40. 40. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 39, wherein the tyrosine kinase inhibitor is afatinib, or a pharma- ceutically acceptable salt thereof.

41. 41. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of any one of claims 37 to 40, wherein the potassium channel inhibitor is clotrimazole, cenicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxillin, penitrem A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylbenzeneacetonitrile, UCL 1684, n-trityl-3-pyridinemethanamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.

42. The CFTR chloride channel inhibitor is (R)-BPO-27, CFTR ｉｎｈ 42. The potassium channel inhibitor or CFTR chloride channel inhibitor, or combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 41, which is selected from the group consisting of benzodiazepine, benzoyl perchlorate, benzoic acid, benzoyl perchlorate ...

43. 43. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 42, wherein the CFTR chloride channel inhibitor is (R)-BPO-27.

44. The cancer is selected from the group consisting of adenoid cystic carcinoma, adrenal gland tumor, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, male breast cancer, carcinomatous tumor, cervical cancer, colorectal cancer, ductal carcinoma, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor-GIST, HER2 positive breast cancer, kidney cancer, laryngeal cancer, leukemia, liver cancer, lobular carcinoma, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant glioma, melanoma, meningioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, multiple myeloma, nasopharyngeal carcinoma, neuroendocrine 44. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 43, which is a tumor, neurobasal cell carcinoma syndrome, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor, parathyroid cancer, penile cancer, peritoneal cancer, pituitary cancer, prostate cancer, renal cell carcinoma, retinoblastoma, salivary gland cancer, sarcoma, skin cancer (non-melanoma), small intestine cancer, gastric cancer, testicular cancer, thyroid cancer, uterine (endometrial) cancer, or vaginal cancer.

45. 45. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 44, wherein the cancer is breast cancer, HER2 positive breast cancer, non-small cell lung cancer (NSCLC), or head and neck cancer.

46. 46. ​​The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 45, wherein the tyrosine kinase inhibitor is administered simultaneously with the potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor.

47. 46. ​​The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 45, wherein the tyrosine kinase inhibitor is administered prior to the potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor.

48. 46. ​​The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 45, wherein the tyrosine kinase inhibitor is administered after the potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor.

49. 49. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to any one of claims 37 to 48, wherein the subject has a mutation in a gene encoding an ErbB family member.

50. 50. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 49, wherein the ErbB gene is epidermal growth factor receptor (EGFR).

51. 51. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 50, wherein the mutation is in exon 18.

52. 52. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 50 or 51, wherein the mutation is in a codon encoding an amino acid at position E709, G719, or a combination thereof.

53. 53. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of claim 52, wherein the mutation encodes E709K, E709A, E709G, E709V, E709H, G719A, G719S, G719C, G719D, G719V, or a combination thereof.

54. 52. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 50 or 51, wherein the mutation comprises a deletion of exon 18.

55. 55. The potassium channel inhibitor or CFTR chloride channel inhibitor, or the combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, according to claim 54, wherein the exon 18 deletion is DelE709_T710insD.

56. 56. The potassium channel inhibitor or CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR chloride channel inhibitor, of any one of claims 7, 8, 14, 15, 21, 22, 28, 29, 35, 36, 42, 43, or 44-55, wherein the (R)-BPO-27 is administered as a racemic mixture with (S)-BPO-27.

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