Compositions and methods for treating cancer

Abstract

Described herein are methods of treating cancer m a subject by administering a therapeutically effective amount of an AP2 associated kinase 1 (AAK1 ) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. -Also disclosed herein are methods of enhancing the responsiveness of a cancer cell to a taxane or a vinca alkaloid, and methods of increasing the efficacy of a taxane or a vinca alkaloid in a subject with cancer by administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. Hie methods can be useful in subjects with cancer that are resistant to the taxane or a vinca alkaloid prior to the administration of the AAK1 inhibitor.

Description

[0001] Attorney’s Docket No.: 21105.0098P1 COMPOSITIONS AND METHODS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No.63 / 667,165, filed on July 3, 2024. The content of this earlier filed application is hereby incorporated by reference in its entirety. BACKGROUND Ovarian cancer remains the most lethal gynecologic cancer. Treatment strategies developed over the past four decades, however, have achieved limited success, evidenced by 5-year survival improving from 40% in 1985 to a still parlous 45% today (Matulonis, U. A. et al. Nat Rev Dis Primers 2, 16061 (2016)). The results of many clinical trials for ovarian cancer have been disappointing. Other than PARP inhibitors approved for maintenance therapy, no approved first line targeted therapy is available for ovarian cancer, largely due to the lack of actionable oncogenic mutations. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1 / PD-L1 antibodies have also shown limited efficacy for ovarian cancer (Barber, E. and Matei, D. Lancet Oncol 22, 903-905, (2021); and Chardin, L. and Leary, A. Front Oncol 11, 795547, (2021)). The current standard of care is surgical debulking followed by paclitaxel / platinum-based chemotherapy (Seward, S. M. and Winer, I. Cancer metastasis reviews 34, 5-10 (2015)). Although patients respond initially, most will relapse due to rapid development of chemotherapy resistance, the mechanism of which is still largely unknown. Therefore, identification of pathways activated by paclitaxel / platinum treatment will lead to better patient stratification. Thus, new treatment strategies are needed. SUMMARY Disclosed herein are methods of treating cancer in a subject, the methods comprising: administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. Disclosed herein are methods of enhancing the responsiveness of a cancer cell to a taxane or a vinca alkaloid, the methods comprising contacting the cancer cell with a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) and a therapeutically effective amount of a taxane or a vinca alkaloid. Disclosed herein are methods of increasing the efficacy of a taxane or a vinca alkaloid in a subject with cancer, the methods comprising: administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. Attorney’s Docket No.: 21105.0098P1 Disclosed herein are methods comprising: a) obtaining or having obtained a sample comprising tumor cells from a cancer patient; b) determining the level of AP2 associated kinase 1 (AAK1) in the tumor cells of the sample; c) identifying the cancer patient as a suitable candidate for treatment with an AAK1 inhibitor and a taxane or a vinca alkaloid, when the level of AAT1 is higher than a level of AAT1 in a control sample and identifying the cancer patient as an unsuitable candidate for treatment with a composition comprising the AAK1 inhibitor and the taxane or the vinca alkaloid, when the level of AAT1 is the same or lower than a level in a control sample; and d) administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid to the cancer patient identified as the suitable candidate, and not administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid to the cancer patient identified as the unsuitable candidate. Other features and advantages of the present compositions and methods are illustrated in the description below, the drawings, and the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 shows schematic diagram of the interaction between paclitaxel and AAK1. FIGS.2A-C show that RNAi screening identifies AAK1 as a synthetic lethal target for platinum treatment in ovarian cancer. FIG.2A shows that screen testing 781 genes using 100 ng / ml of Paclitaxel. Cell viability was assessed by CellTiter-Glo assay. FIGS.2B and 2C show Kaplan-Meier survival analysis of taxane-treated patients in TCGA. FIGS.3A-F show that targeting AAK1 sensitizes paclitaxel treatment in ovarian cancer. FIG.3A shows ES2 cells were transduced with two AAK1 shRNA clones followed by paclitaxel treatment for 72 hours. Paclitaxel IC50were determined by cell viability. FIG. 3B shows the AAK1 knockdown effect on paclitaxel sensitivity in additional ovarian cancer cell lines. FIG.3C shows the AAK1 knockdown effect on Docetaxel sensitivity. FIGS.3D-E show ES2 cells with control vector or AAK1 shRNA were treated with paclitaxel (50nM) for 72 hours, and cell cycle / mitotic entry cycle (FIG.3D) and apoptosis (FIG.3E) were quantified by flow cytometric analysis of p-Histone H3 / 7AAD and Annexin V / PI, respectively. FIG.3F shows a xenograft assay using vector control and AAK1 knockout cells with or without paclitaxel treatment (20mg / kg). FIG.4 shows AAK1 promotes paclitaxel resistance through kinase-dependent function. In vitro AAK1 kinase assay using AAK1 WT or K74A (KA, kinase dead; left Attorney’s Docket No.: 21105.0098P1 panel). AAK1 wild-type, but not kinase dead, rescues paclitaxel IC50in AAK1 knockdown ES2 cells (right panel). FIGS.5A-G show that CDK1 directly phosphorylates AAK1. FIG.5A shows ES2 cells were treated with paclitaxel or nocodazole for 24h, followed by in vitro AAK1 kinase assay. FIG.5B shows ES2 cells were treated with paclitaxel, followed by FLAG IP and WB using different kinase substrate motif antibodies. FIGS.5C-D show CDK1 inhibitors RO3306 (RO) or AZD5438 (AZD) blocked the paclitaxel-induced AAK1 phosphorylation (FIG.5C) and kinase activity (FIG.5D). FIGS.5E-F show in vitro kinase assay using recombinant AAK1 and CDKs. AAK1 phosphorylation (FIG.5E) and kinase activity (FIG.5F) were determined. FIG. 5G shows proximity ligation assay in ES2 cells treated with or without paclitaxel for 24h using rabbit anti-AAK1 and mouse anti-CDK1. FIGS.6A-F show that CDK1-mediated AAK1 T389 phosphorylation promotes AAK1 activity and paclitaxel resistance. FIG.6A shows ES2 cells expressing AAK1 wild- type or T389A were treated with or without paclitaxel for 24h, followed by FALG IP, kinase assay and WB. FIG.6B show in vitro CDK1 kinase assay using AAK1 WT or T389A as substrate. AAK1 activity and phosphorylation were determined. FIG.6C shows specificity confirmation of AAK1 p-T389 antibody. FIG.6D shows ES2 cells were treated with paclitaxel and RO3306, followed by WB. FIG.6E shows AAK1 WT but not T389A promotes paclitaxel resistance. FIG.6F shows IHC analysis of AAK1 p-T389 level in ovarian cancer patient samples who received taxane-based chemotherapy. Resistant: patient recurred within 6 months. Sensitive: patient did not recur within 6 months. FIG.7 shows phospho-proteomic analysis of ES2 cells with or without AAK1 KO and paclitaxel treatment. FIGS.8A-B show targeting AAK1 with small molecular AAK1 inhibitor sensitized ovarian cancer to paclitaxel. FIG.8A shows that ES2 cells were treated with two different AAK1 inhibitors and paclitaxel (taxol), and sensitivity was determined by cell viability assay. FIG.8B shows Xenograft assay using ES2-luciferase cells. Mice were treated with paclitaxel (20mg / kg), AAK1 inhibitor LP935509 (30mg / kg) or combination. FIGS.9A-E show small molecular AAK1 inhibitors sensitize ovarian cancer to taxane. FIG.9A shows ES2 cells were treated with four different AAK1 inhibitors and paclitaxel sensitivity was determined by cell viability (72h). LP935509:1 μM. LP922761: 2 μM. LX9211: 500nM. SGC-AAK1-1: 2 μM. FIG.9B shows ES2 cells expressing vector or AAK1 shRNA were treated with LP935509 (2 μM), followed by cell viability assay. FIG.9C shows LP935509 sensitized paclitaxel in a panel of ovarian cancer patient-derived organoids, Attorney’s Docket No.: 21105.0098P1 primary cancer cells and cell lines. FIGS.9D-E shows xenograft using ES2-luciferase cells (FIG.9D) or ovarian cancer PDX (FIG.9E). Mice were treated with paclitaxel (20 mg / kg, i.p, weekly), LP935509 (30 mg / kg, i.p., daily) or combo. FIG.10 shows AAK1 mRNA levels in tumor vs adjacent normal tissue in ovarian cancer patient samples. FIGS.11A-G show that targeting AAK1 sensitizes paclitaxel treatment in ovarian cancer. FIG.11A shows ES2 cells were transduced with two AAK1 shRNA clones followed by paclitaxel treatment for 72 hours. Paclitaxel IC50were determined by cell viability. FIGS. 11B-D show the AAK1 knockdown effect on paclitaxel sensitivity in ovarian cancer cell lines (FIGS.11B-C) and ovarian cancer patient-derived organoids. FIGS.11E-G show the AAK1 knockdown effect on the sensitivity of docetaxel (FIG.11E), vincristine (FIG.11F) and cisplatin (FIG.11G) in ES2 cells. FIG.12 shows paclitaxel induces caspase-mediated AAK1 cleavage. MDR activity in ES2 cells with or without AAK1 knockdown is shown. DETAILED DESCRIPTION Many modifications and other embodiments of the present disclosure set forth herein will come to mind to one skilled in the art to which this disclosure pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the present disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Before the present compositions and methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, example methods and materials are now described. Moreover, it is to be understood that unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that Attorney’s Docket No.: 21105.0098P1 the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, and the number or type of aspects described in the specification. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosures. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. Definitions As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.” “Comprising” can also mean “including but not limited to.” As used in the specification and the appended claims, the singular forms “a,” “an” and “the” can include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes mixtures of compounds; reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like. The word “or” as used herein means any one member of a particular list and also includes any combination of members of that list. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances where it does not. As used herein, the term “sample” is meant a tissue or organ from a subject; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g., a polypeptide or nucleic acid), which is assayed as described herein. A sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components. As used herein, the term “subject” refers to the target of administration, e.g., a human. The subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a Attorney’s Docket No.: 21105.0098P1 reptile, or an amphibian. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). In some aspects, a subject is a mammal. In some aspects, a subject is a human. The term does not denote a particular age or sex. Thus, adult, child, adolescent and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. As used herein, the term “patient” refers to a subject afflicted with a disease or disorder (e.g., cancer). The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the “patient” has been diagnosed with a need for treatment for cancer, such as, for example, prior to the administering step. Ranges can be expressed herein as from “about” or “approximately” one particular value, and / or to “about” or “approximately” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” or “approximately,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. “Inhibit,” “inhibiting” and “inhibition” mean to diminish or decrease an activity, response, condition, disease, or other biological parameter. This can include, but is not limited to, the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% inhibition or reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, in an aspect, the inhibition or reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. In an aspect, the inhibition or reduction is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100% as compared to native or control levels. In an aspect, the inhibition or reduction is 0-25, 25-50, 50-75, or 75-100% as compared to native or control levels. Attorney’s Docket No.: 21105.0098P1 “Modulate”, “modulating” and “modulation” as used herein mean a change in activity or function or number. The change may be an increase or a decrease, an enhancement or an inhibition of the activity, function or number. As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, relieving, delaying onset of, inhibiting or slowing progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. Treatment can also be administered to a subject to ameliorate one more signs of symptoms of a disease, disorder, and / or condition. For example, the disease, disorder, and / or condition can be relating to cancer. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, certain changes and modifications may be practiced within the scope of the appended claims. Given the fact that protein kinases play important roles in the regulation of pro- survival signaling, a kinome-wide shRNA screening was employed and AP2 associated kinase 1 (AAK1) was identified as a “synthetic lethal” partner of paclitaxel. AAK1 has been reported to function as a regulator of clathrin-dependent endocytosis (Agajanian, M. J. et al. Cell Rep 26, 79-93 e78 (2019); and Conner, S. D. and Schmid, S. L. J Cell Biol 162, 773-779 (2003)). Nonetheless, little is known about the biological role of AAK1 in cancer. TCGA data mining revealed that high AAK1 levels are associated with poor overall and progression- free survival in paclitaxel-treated ovarian cancer patients. As progression-free survival is an excellent indictor of paclitaxel responsiveness in patients, the inverse correlation between AAK1 expression and progression-free survival strongly suggest that ovarian cancer patients with high AAK1 expression are poor responders of paclitaxel-based chemotherapy. Consistently, silencing AAK1 sensitized a panel of ovarian cancer cell lines to paclitaxel treatment in vitro and in vivo. In addition, expressing wild-type but not kinase-dead mutant of Attorney’s Docket No.: 21105.0098P1 AAK1 conferred paclitaxel resistance, demonstrating an important role for AAK1 kinase activity in promoting paclitaxel resistance. Interesting, phospho motif profiling and phospho- mass spectrometry studies identified CDK1 as an important upstream kinase that directly phosphorylates AAK1 at T389 to promote AAK1 kinase activity. As paclitaxel treatment induces prolonged CDK1 activation, the results demonstrate that paclitaxel-induced CDK1 hyperactivation activates AAK1, leading to paclitaxel resistance and treatment failure. Indeed, empowered by an in-house developed phospho-specific antibody (AAK1 pT389), a patient cohort who received paclitaxel-based chemotherapy was assessed, and it was found that AAK1 pT389 level in this patient was positively associated with paclitaxel resistance, showing the use of AAK1 pT389 as a predictive marker for paclitaxel response in ovarian cancer. Therefore, it was assessed whether in response to paclitaxel, CDK1 directly phosphorylates AAK1 at T389 and activates its kinase activity, which promotes cell survival and paclitaxel resistance. Collectively, these findings identified AAK1 as a target to improve paclitaxel efficacy in ovarian cancer. Indeed, small molecule AAK1 inhibitors were shown to significantly sensitize ovarian cancer cells to paclitaxel in vitro and in vivo. The role of CDK1-AAK1 signaling in driving paclitaxel resistance was characterized and AAK1 was validated as a therapeutic target to improve paclitaxel efficacy in ovarian cancer (FIG.1). As discussed herein, AAK1 plays an important role in mediating taxane resistance and small molecular AAK1 inhibitors significantly sensitize cancer cells to taxane treatment. Thus, disclosed herein are methods of treating cancer, enhancing the responsiveness of cancer cells to taxane or vinca alkaloid treatment, and increasing the efficacy of taxane or vinca alkaloid treatment in a subject with cancer comprising administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid or contacting the cancer cell with a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. Compositions and Pharmaceutical Compositions Disclosed herein are compositions useful in the methods described herein. In some aspects, the disclosed compositions are useful in treating cancer. In some aspects, the disclosed compositions are useful in enhancing the responsiveness of a cancer cell to a tubulin inhibitor. In some aspects, the disclosed compositions are useful in increasing the efficacy of a tubulin inhibitor in a subject with cancer. In some aspects, the tubulin inhibitor can be a taxane. In some aspects, the disclosed compositions are useful in enhancing the Attorney’s Docket No.: 21105.0098P1 responsiveness of a cancer cell to a taxane or a vinca alkaloid. In some aspects, the disclosed compositions are useful in increasing the efficacy of a taxane or a vinca alkaloid in a subject with cancer. Any of the compounds or compositions disclosed herein can further comprise a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical compositions can further comprise a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” refers to solvents, dispersion media, coatings, antibacterial, isotonic and absorption delaying agents, buffers, excipients, binders, lubricants, gels, surfactants that can be used as media for a pharmaceutically acceptable substance. The pharmaceutically acceptable carriers can be lipid-based or a polymer-based colloid. Examples of colloids include liposomes, hydrogels, microparticles, nanoparticles and micelles. The compositions can be formulated for administration by any of a variety of routes of administration, and can include one or more physiologically acceptable excipients, which can vary depending on the route of administration. Any of the compounds or compositions described herein can be administered in the form of a pharmaceutical composition. As used herein, the term “excipient” means any compound or substance, including those that can also be referred to as “carriers” or “diluents.” Preparing pharmaceutical and physiologically acceptable compositions is considered routine in the art, and thus, one of ordinary skill in the art can consult numerous authorities for guidance if needed. The compositions can also include additional agents (e.g., preservatives). The pharmaceutical compositions as disclosed herein can be prepared for oral or parenteral administration. Pharmaceutical compositions prepared for parenteral administration include those prepared for intravenous (or intra-arterial), intramuscular, subcutaneous, intrathecal or intraperitoneal administration. Paternal administration can be in the form of a single bolus dose, or may be, for example, by a continuous pump. In some aspects, the compositions can be prepared for parenteral administration that includes dissolving or suspending the disclosed compound in an acceptable carrier, including but not limited to an aqueous carrier, such as water, buffered water, saline, buffered saline (e.g., PBS), and the like. One or more of the excipients included can help approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like. Where the compositions include a solid component (as they may for oral administration), one or more of the excipients can act as a binder or filler (e.g., for the formulation of a tablet, a capsule, and the like). Where the compositions Attorney’s Docket No.: 21105.0098P1 are formulated for application to the skin or to a mucosal surface, one or more of the excipients can be a solvent or emulsifier for the formulation of a cream, an ointment, and the like. The compositions disclosed herein can be formulated in a variety of combinations. In some aspects, the compositions can comprise an AP2 associated kinase 1 (AAK1) inhibitor and a taxane or a vinca alkaloid. In some aspects, the taxane can be the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane. In some aspects, the vinca alkaloid can be vinblastine, vinorelbine, vincristine, vinflunine, or vindesine. In some aspects, the AAK1 inhibitor can be LX9211 or LP935509, LP922761, or SGC-AAK1-1. In some aspects, the AAK1 inhibitor can be any of the AAK1 inhibitors in Table 1.

[0002] Attorney’s Docket No.: 21105.0098P1 Table 1. AAK1 inhibitors. Attorney’s Docket No.: 21105.0098P1 The particular combination of the taxane or the vinca alkaloid with an AAK1 inhibitor can vary according to many factors, for example, the particular the type and severity of the cancer. The compositions described herein can be formulated to include a therapeutically effective amount of the taxane or the vinca alkaloid in combination with the AAK1 inhibitor. In some aspects, the taxane or the vinca alkaloid and the AAK1 inhibitor can be contained within a pharmaceutical formulation separately or in combination (e.g., together). In some aspects, the pharmaceutical formulation can be a unit dosage formulation. In some aspects, any of the compositions (taxane or the vinca alkaloid, AAK1 inhibitor, or a combination thereof) can be formulated for oral or parental administration. In some aspects, both the taxane or the vinca alkaloid and AAK1 inhibitor can be formulated for oral or parenteral administration. In some aspects, the parenteral administration can be intravenous, subcutaneous, intramuscular or direct injection. Attorney’s Docket No.: 21105.0098P1 In some aspects, the compositions disclosed herein are formulated for oral or parenteral administration. In some aspects, the compositions disclosed herein are formulated for oral, intramuscular, intravenous, subcutaneous, intrathecal, direct injection or intraperitoneal administration. In some aspects, the taxane or the vinca alkaloid and the AAK1 inhibitor can be combined with the administration of chemotherapy or radiation. In some aspects, the chemotherapeutic agent can be cisplatin, carboplatin, or doxorubicin. In some aspects, the chemotherapeutic agent can be a vinca alkaloid. Examples of vinca alkaloids included but are not limited to vinblastine, vinorelbine, vincristine, vinflunine, and vindesine. In some aspects, the AAK1 inhibitor can be combined with a vinca alkaloid. In some aspects, the AAK1 inhibitor can be combined with a vinca alkaloid rather than a taxane. In some aspects, the AAK inhibitor can be combined with other tubulin inhibitors, for example, epothilones. In some aspects, the epothilone can be epothilone B (patupilone), epothilone D (utidelone), or ixabepilone. In some aspects, the AAK inhibitor can be combined with mirvetuximab soravtansine (Elahere; mirvetuximab soravtansine-gynx). In some aspects, the AAK inhibitor can be combined with a kinesin inhibitor. In some aspects, the kinesin inhibitor can be monastrol, ispinesib (SB-715992), or filanesib (Arry- 520). The pharmaceutical compositions can be sterile and sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation, which is encompassed by the present disclosure, can be combined with a sterile aqueous carrier prior to administration. The pH of the pharmaceutical compositions typically will be between 3 and 11 (e.g., between about 5 and 9) or between 6 and 8 (e.g., between about 7 and 8). The resulting compositions in solid form can be packaged in multiple single dose units, each containing a fixed amount of the above- mentioned agent or agents, such as in a sealed package of tablets or capsules. The composition in solid form can also be packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment. The compositions can also be formulated as powders, elixirs, suspensions, emulsions, solutions, syrups, aerosols, lotions, creams, ointments, gels, suppositories, sterile injectable solutions and sterile packaged powders. The active ingredient can be any of the disclosed compounds described herein in combination with one or more pharmaceutically acceptable carriers. As used herein “pharmaceutically acceptable” means molecules and compositions that do not produce or Attorney’s Docket No.: 21105.0098P1 lead to an untoward reaction (i.e., adverse, negative or allergic reaction) when administered to a subject as intended (i.e., as appropriate). The therapeutically effective amount or dosage of any of the disclosed taxanes or the vinca alkaloid or AAK1 inhibitors described herein, and any of the chemotherapeutic agents, used in the methods as disclosed herein, applied to mammals (e.g., humans) can be determined by one of ordinary skill in the art with consideration of individual differences in age, weight, sex, other drugs administered and the judgment of the attending clinician. Variations in the needed dosage may be expected. Variations in dosage levels can be adjusted using standard empirical routes for optimization. The particular dosage of a pharmaceutical composition to be administered to the patient will depend on a variety of considerations (e.g., the severity of the cancer symptoms), the age and physical characteristics of the subject and other considerations known to those of ordinary skill in the art. Dosages can be established using clinical approaches known to one of ordinary skill in the art. In some aspects, the therapeutically effective amount of the taxane or the vinca alkaloid can be administered orally or parentally. In some aspects, the therapeutically effective amount of the AAK1 inhibitor can be administered orally or parentally. In some aspects, the parenteral administration can be intravenous, subcutaneous, intramuscular, or direct injection. The duration of treatment with any composition provided herein can be any length of time from as short as one day to as long as the life span of the host (e.g., many years). For example, the compositions can be administered once a week (for, for example, 4 weeks to many months or years); once a month (for, for example, three to twelve months or for many years); or once a year for a period of 5 years, ten years, or longer. It is also noted that the frequency of treatment can be variable. For example, the present compositions can be administered once (or twice, three times, etc.) daily, weekly, monthly, or yearly. In some aspects, the therapeutically effective dose of any of the taxanes or the vinca alkaloids described herein may be less / lower when combined with any of the AAK1 inhibitors disclosed herein compared to the dose typically administered in the absence of the AAK1 inhibitors disclosed herein. In some aspects, the administration of any of the AAK1 inhibitors disclosed herein can increase the efficacy of any of the taxanes or the vinca alkaloids described herein. In some aspects, the therapeutically effective dose of any of the chemotherapeutic agents described herein may be less / lower when combined with any of the AAK1 inhibitors disclosed herein compared to the dose typically administered in the absence of the AAK1 Attorney’s Docket No.: 21105.0098P1 inhibitors disclosed herein. In some aspects, the administration of any of the AAK1 inhibitors disclosed herein can increase the efficacy of any of the chemotherapeutic agents described herein. The total effective amount of the AAK1 inhibitors, taxanes or the vinca alkaloids, or chemotherapeutic agents as disclosed herein can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol in which multiple doses are administered over a more prolonged period of time. Alternatively, continuous intravenous infusions sufficient to maintain therapeutically effective concentrations in the blood are also within the scope of the present disclosure. The compositions (e.g., taxane or the vinca alkaloid, AAK1 inhibitors) described herein can be administered in conjunction with other therapeutic modalities to a subject in need of therapy. The present compounds can be given to prior to, simultaneously with or after treatment with other agents or regimes. For example, any of the taxanes or the vinca alkaloids and AAK1 inhibitors disclosed herein can be administered in conjunction with standard therapies used to treat cancer (e.g., a chemotherapeutic agent). In some aspects, any of the taxanes or the vinca alkaloids and / or the AAK1 inhibitors disclosed herein can be co- formulated with a chemotherapeutic agent. In some aspects, any of the taxanes or the vinca alkaloid disclosed herein can be co-formulated with any of the AAK1 inhibitors disclosed herein. In some aspects, the chemotherapeutic agent can also be a vinca alkaloid. Any of the compositions (e.g., taxanes or the vinca alkaloids and AAK1 inhibitors) described herein can be administered as a “combination.” In some aspects, the taxane or the vinca alkaloid and the AAK1 inhibitor can be administered as a combination with a chemotherapeutic agent. It is to be understood that, for example, any of the taxanes or the vinca alkaloids and AAK1 inhibitors disclosed herein can be provided to the subject in need, either prior to administration of a chemotherapeutic agent or any combination thereof, concomitant with administration of said chemotherapeutic agent or any combination thereof (co-administration) or shortly thereafter. The dosage to be administered depends on many factors including, for example, the route of administration, the formulation, the severity of the patient's condition / disease, previous treatments, the patient's size, weight, surface area, age, and gender, other drugs being administered, and the overall general health of the patient including the presence or absence of other diseases, disorders or illnesses. Dosage levels can be adjusted using standard empirical methods for optimization known by one skilled in the art. Administrations Attorney’s Docket No.: 21105.0098P1 of the compositions described herein can be single or multiple (e.g., 2- or 3-, 4-, 6-, 8-, 10-, 20-, 50-, 100-, 150-, or more fold). Further, encapsulation of the compositions in a suitable delivery vehicle (e.g., polymeric microparticles or implantable devices) can improve the efficiency of delivery. Method of Treatment The methods disclosed herein can be useful for the treatment of a subject with cancer. Disclosed herein are methods of treating cancer in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid. In some aspects, the taxane or the vinca alkaloid can be administered prior to, concurrently or sequentially with the therapeutically effective amount the AAK1 inhibitor. In some aspects, the subject can exhibit intrinsic or an acquired resistance to the taxane or the vinca alkaloid. In some aspects, the therapeutically effective amount the taxane or the vinca alkaloid can be administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the AAK1 inhibitor can reduce the dose of the taxane or the vinca alkaloid by 1, 2, 3, 4, or 5 fold. In some aspects, the taxane or the vinca alkaloid can be administered at a dose can be 1, 2, 3, 4, or 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the taxane or the vinca alkaloid and the AAK1 inhibitor can achieve improved efficacy and / or extend the survival of subjects compared to administration of the taxane or the vinca alkaloid alone (e.g., without the AAK1 inhibitor). In some aspects, the cancer can be associated with elevated levels of AP2 associated kinase 1 (AAK1) prior to the administration of the AAK1 inhibitor. In some aspects, the cancer can be ovarian cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma. Also disclosed herein are methods of enhancing the responsiveness of a cancer cell to a taxane or a vinca alkaloid. In some aspects, the methods can comprise contacting the cancer cell with a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) and a therapeutically effective amount of a taxane or a vinca alkaloid. In some aspects, the taxane or the vinca alkaloid can be administered prior to, concurrently or sequentially with the therapeutically effective amount the AAK1 inhibitor. In some aspects, the therapeutically effective amount of the taxane or the vinca alkaloid can be administered prior to, Attorney’s Docket No.: 21105.0098P1 concurrently or sequentially administering the therapeutically effective amount the AAK1 inhibitor. In some aspects, the cancer cell was resistance to the taxane or the vinca alkaloid prior to the administration of the AAK inhibitor. In some aspects, the cancer cells can be human cancer cells. In some aspects, the cancer cell can be in a subject. In some aspects, the cancer cell is an ovarian cancer cell, a lung cancer cell, a breast cancer, a head and neck cancer cell, a pancreatic cancer cell, a prostate cancer cell, an endometrial cancer cell, a gastric cancer cell, a bladder cancer cell, an anaplastic thyroid cancer cell, a cervical cancer cell, or a melanoma cancer cell. In some aspects, the therapeutically effective amount the taxane or the vinca alkaloid can be administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the AAK1 inhibitor can reduce the dose of the taxane or the vinca alkaloid by 1, 2, 3, 4, or 5 fold. In some aspects, the taxane or the vinca alkaloid can be administered at a dose that can be 1, 2, 3, 4, or 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the taxane or the vinca alkaloid and the AAK1 inhibitor can achieve improved efficacy and / or extend the survival of subjects compared to administration of the taxane or the vinca alkaloid alone (e.g., without the AAK1 inhibitor). In some aspects, the cancer can be associated with elevated levels of AP2 associated kinase 1 (AAK1) prior to the administration of the AAK1 inhibitor. Further disclosed herein are methods of increasing the efficacy of a taxane or the vinca alkaloid in a subject with cancer. In some aspects, the method can comprise: administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or the vinca alkaloid. In some aspects, the taxane or the vinca alkaloid can be administered concurrently or sequentially with the therapeutically effective amount the AAK1 inhibitor. In some aspects, the subject can exhibit intrinsic or an acquired resistance to the taxane or the vinca alkaloid. In some aspects, the subject can be taxane or the vinca alkaloid naïve. In some aspects, the subject has cancer. In some aspects, the cancer can be ovarian cancer, lung cancer (e.g., non- small cell lung cancer), breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma. In some aspects, the therapeutically effective amount the taxane or the vinca alkaloid can be administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the AAK1 inhibitor can reduce the dose of the taxane or the vinca alkaloid Attorney’s Docket No.: 21105.0098P1 by 1, 2, 3, 4, or 5 fold. In some aspects, the taxane or the vinca alkaloid can be administered at a dose that can be 1, 2, 3, 4, or 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the taxane or the vinca alkaloid and the AAK1 inhibitor can achieve improved efficacy and / or extend the survival of subjects compared to administration of the taxane or the vinca alkaloid alone (e.g., without the AAK1 inhibitor). In some aspects, the cancer can be associated with elevated levels of AP2 associated kinase 1 (AAK1) prior to the administration of the AAK1 inhibitor. In some aspects, the taxane can be paclitaxel, docetaxel, cabazitaxel, or abraxane. In some aspects, the vinca alkaloid can be vinblastine, vinorelbine, vincristine, vinflunine, or vindesine. In some aspects, the AAK1 inhibitor can be any of the AAK1 inhibitors provided in Table 1. In some aspects, the AAK1 inhibitor can be LP-935509, BMT-090605, LP-922761, BMT-124110, LP-927443, BMS-901715, or BMS-986176 (LX9211). In some aspects, the methods can further comprise administering chemotherapy or radiation to the subject. In some aspects, the chemotherapy can be a chemotherapeutic agent. In some aspects, the chemotherapeutic agent can be cisplatin, carboplatin, or doxorubicin. In some aspects, the chemotherapeutic agent can be a vinca alkaloid. Vinca alkaloid drugs are a type of mitotic inhibitor and a type of antimicrotuble agent. Examples of vinca alkaloids included but are not limited to vinblastine, vinorelbine, vincristine, vinflunine, and vindesine. In some aspects, the methods also include the step of administering a therapeutic effective amount of any of the compositions disclosed herein. In some aspects, compositions can comprise a taxane or the vinca alkaloid. In some aspects, compositions can comprise an AAK1 inhibitor. In some aspects, compositions can comprise a chemotherapeutic agent. In some aspects, the cell can be a mammalian or a human cell. In some aspects, the cell can be a cancer cell. In some aspects, the methods can further include the step of identifying a subject (e.g., a human patient) as being in need of treatment before the administration step. In some aspects, the subject has been diagnosed with cancer prior to the administering step. In some aspects, the subject has been identified as having elevated AP2 associated kinase 1 (AAK1) levels. In some aspects, the subject has a cancer. In some aspects, the cancer can be a primary or a secondary tumor. In some aspects, the cancer can be a solid tumor. In some aspects, the cancer can be a non-solid tumor. In some aspects, the primary or secondary Attorney’s Docket No.: 21105.0098P1 tumor can be within the subject’s ovary, breast, pancreas, lung, prostate, head or neck, prostrate, endometrium, stomach, bladder, thyroid, cervix, or skin. In some aspects, the cancer can ovarian cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma. Disclosed herein are methods, comprising: a) obtaining or having obtained a sample comprising tumor cells from a cancer patient; b) determining the level of AP2 associated kinase 1 (AAK1) in the tumor cells of the sample; c) identifying the cancer patient as a suitable candidate for treatment with an AAK1 inhibitor and a taxane or the vinca alkaloid, when the level of ATT1 is higher than a level of ATT1 in a control sample and identifying the cancer patient as an unsuitable candidate for treatment the AAK1 inhibitor and the taxane or the vinca alkaloid, when the level of ATT1 is the same or lower than a level in a control sample; and d) administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or the vinca alkaloid to the cancer patient identified as the suitable candidate, and not administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or the vinca alkaloid to the cancer patient identified as the unsuitable candidate. In some aspects, the sample can be a biopsy. In some aspects, the therapeutically effective amount of the AAK1 inhibitor and the therapeutically effective amount of taxane or the vinca alkaloid can be administered orally or parentally. In some aspects, the parenteral administration is intravenous, subcutaneous, intramuscular, or direct injection. In some aspects, the taxane or the vinca alkaloid can be administered concurrently or sequentially with the therapeutically effective amount the AAK1 inhibitor. In some aspects, the therapeutically effective amount the taxane or the vinca alkaloid can be administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the administration of the AAK1 inhibitor can reduce the dose of the taxane or the vinca alkaloid by 1, 2, 3, 4, or 5 fold. In some aspects, the taxane or the vinca alkaloid can be administered at a dose that can be 1, 2, 3, 4, or 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone. In some aspects, the cancer patient has ovarian cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma. In some aspects, the taxane can be paclitaxel, docetaxel, cabazitaxel, or abraxane. Attorney’s Docket No.: 21105.0098P1 In some aspects, the vinca alkaloid can be vinblastine, vinorelbine, vincristine, vinflunine, or vindesine. In some aspects, the AAK1 inhibitor can be any of the AAK1 inhibitors provided in Table 1. In some aspects, the AAK1 inhibitor can be LP-935509, BMT-090605, LP-922761, BMT-124110, LP-927443, BMS-901715, or BMS-986176 (LX9211). The therapeutically effective amount can be the amount of the taxane or the vinca alkaloid and the amount of the AAK1 inhibitor administered to a subject that leads to a full resolution of the symptoms of the condition or disease, a reduction in the severity of the symptoms of the condition or disease, or a slowing of the progression of symptoms of the condition or disease. The methods described herein can also include a monitoring step to optimize dosing. The compositions described herein can be administered as a preventive treatment or to delay or slow the progression of the condition or disease (e.g., cancer). The compositions disclosed herein can be formulated in a variety of combinations. The particular combination of the taxanes or the vinca alkaloids disclosed herein with the AAK1 inhibitors disclosed herein can vary according to many factors, for example, the particular the type and severity of the cancer. The particular combination of the taxanes or the vinca alkaloids and AAK1 inhibitors disclosed herein with one or more chemotherapeutic agents (e.g., cisplatin, carboplatin, or doxorubicin) can also vary according to many factors, for example, the particular the type and severity of the cancer. The compositions described herein can be formulated to include a therapeutically effective amount of any of the taxanes or the vinca alkaloids disclosed herein alone, any of the AAK1 inhibitors disclosed herein alone or in combination; and optionally, in further combination with a chemotherapeutic agent. In some aspects, a taxane or a vinca alkaloid and / or an AAK1 inhibitor can be contained within a pharmaceutical formulation. In some aspects, the pharmaceutical formulation can be a unit dosage formulation. In some aspects, the methods disclosed herein also include treating a subject with cancer, enhancing the responsiveness of a cancer cell to a taxane or a vinca alkaloid, or increasing the efficacy of a taxane or a vinca alkaloid in a subject with cancer. In some aspects, the methods disclosed herein can include the step of determining AAK1 levels or expression in a subject. In some aspects, the methods described herein can further comprise administering a therapeutically effective amount of a chemotherapeutic agent to the subject. In some aspects, the chemotherapeutic agent can be a vinca alkaloid. In some aspects, the chemotherapeutic agent can be paclitaxel, docetaxel, cabazitaxel, or abraxane. Attorney’s Docket No.: 21105.0098P1 In some aspects, the therapeutically effective amount of the taxane or the vinca alkaloid can be administered orally or parentally. In some aspects, the therapeutically effective amount of the AAK1 inhibitor can be administered orally or parentally. In some aspects, the parenteral administration can be intravenous, subcutaneous, intramuscular, or direct injection Kits Disclosed herein are kits that comprise a taxane or a vinca alkaloid and an AAK1 inhibitor described herein and suitable instructions (e.g., written and / or provided as audio-, visual-, or audiovisual material). In some aspects, the kit comprises a predetermined amount of a taxane or a vinca alkaloid and an AAK1 inhibitor or pharmaceutical composition thereof. In some aspects, the kit can further comprise one or more of the following: instructions, sterile fluid, syringes, a sterile container, delivery devices, and buffers or other control reagents. EXAMPLES Example 1: The role of AAK1 in paclitaxel resistance. Kinome-wide RNAi screening identifies AAK1 as the synthetic lethal partner for paclitaxel treatment. To identify kinases that play a role in chemotherapy resistance, kinome- wide RNAi screening was performed using a lentiviral shRNA library targeting 781 human kinase genes (4,518 clones) to test cisplatin and paclitaxel, two of the most widely used chemotherapy agents. The primary screen involved transducing cisplatin- and paclitaxel- resistant human cancer cells, KB-3-1cisR and KB-3-1TaxolR, with a lentivirus pool containing shRNAs targeting each of the 781 individual genes, and treating with sublethal doses of cisplatin or paclitaxel. From the paclitaxel screening arm, AAK1 was identified as a candidate for mediating paclitaxel resistance (FIG.2A). High AAK1 expression is associated with poor paclitaxel response in ovarian cancer. To identify the cancer type AAK1 may play an important role in mediating paclitaxel resistance, the association between AAK1 expression and patient survival was analyzed using data of paclitaxel-treated patient population from TCGA database. Strikingly, in TCGA ovarian serous adenocarcinoma dataset, high AAK1 expression is shown to be correlated with both poor overall survival (FIG.2B) and progression-free survival (FIG.2C). Since progression-free survival is an excellent indictor of paclitaxel responsiveness in paclitaxel- treated patients, an inverse correlation between AAK1 expression and progression-free survival shows that HGSOC patients with high AAK1 expression are poor responders of paclitaxel-based chemotherapy. Attorney’s Docket No.: 21105.0098P1 AAK1 is important for ovarian cancer cell survival and tumor growth in the presence of paclitaxel. It was tested whether AAK1 regulates cellular response to paclitaxel. Indeed, silencing AAK1 in multiple ovarian cancer cell lines including paclitaxel resistant subline greatly sensitized cells to taxanes such as paclitaxel (FIGS.3A-3B) and docetaxel (FIG.3C). AAK1 silencing led to G2 / M cell cycle arrest and enhanced apoptosis in the presence of paclitaxel (FIGS.3D-3E). In vivo xenograft assay further demonstrated that AAK1 silencing sensitizes ovarian cancer cells to paclitaxel in vivo (FIG.3F). Collectively, these results demonstrate that AAK1 plays an important role in regulating paclitaxel response in ovarian cancer. CDK1 directly phosphorylates AAK1 at T389 to activate AAK1 kinase activity. It was investigated whether kinase activity of AAK1 is important for paclitaxel resistance. shRNA- resistant wild-type and kinase-dead AAK1 construct (K76A, KA, FIG.4) were generated. Cell viability showed that wild-type, but not kinase-dead AAK1, restored IC50of paclitaxel in AAK1-knockdown ES2 to the level seen in control cells (FIG.4), demonstrating that kinase activity of AAK1 confers paclitaxel resistance. Given that paclitaxel treatment induces M phase arrest and hyperactivation of CDK1, and AAK1 activity is also elevated upon paclitaxel treatment (FIG.5A), it was tested whether CDK1 serves as an upstream activator for AAK1 in the presence of paclitaxel. Indeed, using a panel of kinase substrate phospho- motif antibodies, it was found that paclitaxel treatment induced AAK1 phosphorylation with CDK1 substrate motif (FIG.5B). ADP-Glo kinase activity assay coupled with western blotting analysis further revealed that paclitaxel treatment promoted AAK1 phosphorylation (FIG.5C) and kinase activity (FIG.5D), which can be blocked by CDK1 inhibitors RO3306 or AZD5438. In vitro kinase assay using a panel of CDKs and mitosis related kinases further demonstrated that CDK1 directly phosphorylates AAK1 and increases AAK1 kinase activity (FIGS.5E-5F). Proximity ligation assay showed CDK1 interacts with AAK1, which can be further enhanced by paclitaxel treatment (FIG.5G). These results show that upon paclitaxel treatment, CDK1 directly phosphorylates AAK1 to enhance its kinase activity in ovarian cancer cells. AAK1 T389 phosphorylation is associated with paclitaxel resistance in ovarian cancer. To further delineate the mechanism by which CDK1 activates AAK1 upon paclitaxel treatment, phospho-mass spectrometry analysis was performed and the results show that paclitaxel treatment induces AAK1 T389 phosphorylation in ovarian cancer cells. In addition, phospho-deficient mutant AAK1 (T389A) blunted paclitaxel-induced AAK1 phosphorylation and activation in ES2 cells (FIG.6A), showing that upon paclitaxel treatment, T389 is the Attorney’s Docket No.: 21105.0098P1 phosphorylation site that regulates AAK1 kinase activity. In vitro kinase assay further demonstrated that T389A blunted CDK1-induced AAK1 phosphorylation and activation (FIG.6B), establishing a direct link between CDK1 and AAK1 T389 phosphorylation. a pT389 phospho-specific antibody was generated and its specificity was confirmed (FIG.6C). It was further confirmed that paclitaxel induces AAK1 T389 phosphorylation in CDK1 dependent manner (FIG.6D). Importantly, AAK1 wild-type but not T389A mutant promoted paclitaxel resistance (FIG.6E). To demonstrate the clinical significance of these findings, an ovarian cancer patient cohort sample from a patient who received paclitaxel-based chemotherapy was assessed and, strikingly, immunohistochemistry analysis revealed that AAK1 T389 phosphorylation is associated with paclitaxel resistance (FIG.6F). These data revealed a functional link between CDK1-mediated AAK1 T389 phosphorylation and paclitaxel resistance. Therefore, the data demonstrate that upon paclitaxel treatment, CDK1 directly phosphorylates AAK1 at T389, leading to AAK1 activation and paclitaxel resistance. Therefore, pharmaceutical targeting of AAK1 can be used to improve paclitaxel-based chemotherapy for ovarian cancer. Methods. To reveal the mechanism by which CDK1 activates AAK1 to promote paclitaxel resistance. The data links CDK1 to AAK1 activation upon paclitaxel treatment. As AAK1 kinase activity is important to promote paclitaxel resistance, it can be investigated whether CDK1-mediated AAK1 T389 phosphorylation enhances AAK1 kinase activity to confer paclitaxel resistance in ovarian cancer, and explore the downstream signaling governed by AAK1 to regulate paclitaxel resistance. To examine whether phosphorylation and activation of AAK1 by CDK1 is important for AAK1 to confer paclitaxel resistance in vitro and in vivo. It will be tested whether CDK1- mediated AAK1 T389 phosphorylation promotes AAK1 kinase activity. Recombinant AAK1 WT, T389D and T389A will be purified, and AAK1 in vitro kinase assay will be performed to examine whether T389D can increase and T389A can decrease AAK1 activity in vitro. To directly link CDK1 to AAK1 T389 phosphorylation, CDK1 in vitro kinase assay will be performed using AAK1 WT and T389A as substrate to examine whether T389A can fully or partially block CDK1-mediated AAK1 phosphorylation and activation. AAK1 phosphorylation will be monitored by AAK1 pT389 antibody and CDK phospho-substrate motif antibody. To demonstrate CDK1 can phosphorylate AAK1 at T389 in cells, ovarian cancer cell lines such as ES2, OVCAR8 and PEO1 with AAK1 knockdown and forced expression of AAK1 WT, phospho-mimetic T389D and phospho-deficient T389A will be generated. Similarly with in vitro analysis, it will be examined whether AAK1 T389A can Attorney’s Docket No.: 21105.0098P1 block CDK1-mediated AAK1 phosphorylation and activation. T389D may increase AAK1 activity in vitro, and that T389A mutant may fully block CDK1-mediated AAK1 phosphorylation and activation in vitro and in cells. If T389A partially blunts the effect of CDK1 on AAK1 phosphorylation and activation, it would indicate that CDK1 can phosphorylate additional sites on AAK1 to regulate its activity. If so, the function of another phosphorylation site (T460) which is also identified by the phosphor-mass spectrometry analysis will be examined. It will also be tested whether CDK1-AAK1 contributes to paclitaxel resistance in ovarian cancer in vitro. To test whether CDK1-mediated AAK1 phosphorylation contributes to paclitaxel resistance, ovarian cancer cell lines such as ES2, OVCAR8 and PEO1 with AAK1 knockdown and forced expression of AAK1 WT, phospho-mimetic T389D and phospho-deficient T389A will be generated. Cells will be treated with or without paclitaxel and paclitaxel sensitivity will be examined by paclitaxel IC50 (cell titer glo), cell cycle (propidium iodide), mitotic entry (p-Histone H3) and apoptosis (Annexin V / PI), as shown in FIGS.3A, 3D and 3E. AAK1 T389 phosphorylation and activity will be monitored by WB and ADP-glo kinase assay as in FIGS.6A and 6C. It will be tested whether CDK1-AAK1 contributes to paclitaxel resistance in ovarian cancer in vivo. An athymic nu / nu mice (4-6 week-old, female, 10 mice / group) will be used. Five groups of mice using ES2 cells with, i) empty vectors; ii) AAK1 knockdown; knockdown of AAK1 and expression of AAK1; iii) WT; iv) T389D; and v) T389A will be treated with either paclitaxel (20mg / kg, once a week, IP) or vehicle (PBS) for four weeks. Tumor growth will be monitored once a week using in vivo bioluminescence. p-AAK1 T389, p-CDK1, p-Histone H3, and cleaved-caspase 3 levels will be determined by (IHC) and western blotting at endpoint. It is expected that AAK1 knockdown will sensitize ovarian cancer cells to paclitaxel treatment, while AAK1 T389D but not T389A will rescue the paclitaxel-induced M phase arrest and apoptosis in AAK1 knockdown cells in vitro and in vivo. If expression of T389D achieves partial rescue, this could mean that T389D may not fully mimic the AAK1 T389 phosphorylation. If so, an alternative phosphomimetic mutant (T389E) will be tested. To explore the AAK1 downstream signaling that regulates paclitaxel resistance. To uncover the downstream signaling of AAK1 that confers paclitaxel resistance, important mitosis signaling such as p-Aurora and p-PLK1 was examined. However, no difference was found between control cells and AAK1 knockdown cells. Because the canonical function of AAK1 is to regulate clathrin-dependent endocytosis, the role that AAK1-regulated Attorney’s Docket No.: 21105.0098P1 endocytosis may play in paclitaxel sensitivity in ovarian cancer was assessed. Silencing important endocytosis machinery such as clathrin and AP2, however, had no impact on paclitaxel IC50, arguing against the involvement of endocytosis in regulating paclitaxel sensitivity. To identify the downstream signaling regulated by AAK1, global phospho- proteomics was performed in control and AAK1 KO ES2 cells treated with or without paclitaxel (FIG.7). Interestingly, phosphorylation of several important components of M phase checkpoint including BUB1B and TPX2 were found to be downregulated in AAK1 KO cells. To examine whether targeting AAK1 can improve paclitaxel efficacy in ovarian cancer. The results that silencing AAK1 sensitized ovarian cancer cells to paclitaxel in vitro and in vivo show that AAK1 is a therapeutic target that can be used to improve paclitaxel- based chemotherapy in ovarian cancer. Therefore, AAK1 inhibitor combined with paclitaxel was evaluated in vitro and in vivo. Indeed, two structurally unrelated AAK1 inhibitors, with a concentration that induce no cell death by themselves, robustly sensitized ovarian cancer cells to paclitaxel in vitro and enhanced the efficacy of paclitaxel in vivo (FIGS. 8A-8B). Therefore, various clinically relevant ovarian cancer models established, including a large panel of ovarian cancer cell lines, patient-derived ovarian cancer primary cells, two patient- derived organoids (PDO), two patient-derived xenografts (PDX)( Jin, L. et al. Cancer Cell 34, 315-330 e317, (2018)) and a ovarian cancer syngeneic model (HGS2-luciferase) derived from Brca2− / −;Trp53− / −;Pten− / −GEMM mice (Maniati, E. et al. Cell Rep 30, 525-540 e527, (2020)), to comprehensively evaluate the efficacy of AAK1 inhibitor / paclitaxel combination in ovarian cancer. AAK1 inhibitor / paclitaxel combination will be evaluated in vitro using a collection of ovarian cancer cell lines, primary patient tumor cells and patient-derived organoids. Also, AAK1 inhibitor / paclitaxel combination will be further tested in paclitaxel IC50, apoptosis, cell cycle and mitotic entry as described in FIG.3 using a panel of ovarian cancer cell lines, primary patient tumor cells and PDOs. Levels of p-AAK / AAK1, p-CDK1, p-Histone H3, and cleaved-caspase by WB will also be assed to examine whether AAK1 pT389 can be used to predict the efficacy of AAK1 / paclitaxel combination. It will be determined whether AAK1 / paclitaxel combination is particularly effective in any subtypes of ovarian cancer (HGSOC, LGSOC, OCCC). The AAK1 inhibitor / paclitaxel combination will be evaluated in vivo using patient- derived xenograft models. Previous in vivo studies showed 30 mg / kg / day of AAK1 inhibitor can inhibit AAK1 activity, and in vivo this dosage is well-tolerated in mice. The in vivo cell Attorney’s Docket No.: 21105.0098P1 line study also showed that 30 mg / kg / day of AAK1 inhibitor enhanced paclitaxel efficacy in vivo without systemic toxicity (FIG.8B). Therefore, this dose of AAK1 inhibitor for PDX experiments will be used. PDX tumors will be implanted in the flank of NSG mice (6-week- old, female, 10 group / mice). When tumor sizes reach 150 mm3, the mice will receive vehicle control, single treatment, or combinations as follows: paclitaxel: 20 mg / kg, once / week, i.p.; AAK1 inhibitor 30 mg / kg, daily, i.p. Tumor sizes will be monitored every 3 days. At endpoint, levels of p-AAK1, p-CDK1, p-Histone H3, and cleaved-caspase 3 levels in tumors will be determined by western blot / IHC. AAK1 activity will also be determined by in vitro kinase assay to confirm the effectiveness of inhibitors in vivo. Statistical Analyses. Two-sample t-test will be used to compare tumor mass at the endpoint between each experimental and control group. A mixed model will be used in each set to compare the tumor growth across 4 groups as well as for pairwise comparisons when a significant overall difference exists. An interaction term between AAK1 inhibitor and paclitaxel will be added in the mixed model to test synergistic effect on the tumor growth. ANOVA will be used to compare the expressions of P-AAK1, AAK1, CDK1 and its downstream effectors activities across the 4 groups in each set. Statistical Power. The ratio of the tumor mass between control and experimental group is assumed to be more than 1.5. A sample size of 10 mice per group will achieve at least 80% power at the significance level of 0.05 to detect a difference of 1.5 times in tumor mass between control and experimental group, assuming the coefficient of variation on the original scale is 0.3. It is expected that AAK1 inhibitor / paclitaxel combination will synergistically attenuate cell viability in vitro and tumor growth in vivo. An in vivo experiment (2-3 mice) using AAK1 kinase assay will be carried out to determine the minimal dose that effectively inhibits AAK1 activity. Body weight will be monitored and hematopoietic abnormality in vivo. Example 2: AAK1 as a therapeutic target for ovarian cancer. Taxanes and other anti-tubulin agents remain standard of care for a variety of cancers including ovarian cancer. Therefore, efforts have been made to develop targeted agents that can improve taxane response or reverse taxane resistance. Despite strong preclinical evidence that p-glycoprotein (MDR1) mediates taxane resistance, at least in cell culture setting, numerous clinical trials evaluating MDR1 inhibitors in combination with taxanes have been disappointing and currently there is no FDA-approved agent available to improve taxane response or overcome resistance (Lai, J.-I., et al. Frontiers in Oncology 10, (2020); and Attorney’s Docket No.: 21105.0098P1 Pilotto Heming, C. et al. Heliyon 8, e11171 (2022)). The results described herein that silencing AAK1 sensitized ovarian cancer cells to taxanes and other anti-tubulin agents in vitro and in vivo show that AAK1 is a therapeutic target to improve taxane-based chemotherapy in ovarian cancer. Interestingly, a recent knockout mice screening study found that AAK1 knockout mice show reduced pain response, which led to the preclinical / clinical development of AAK1 inhibitor to treat neuropathic pain (Kostich, W. et al. J Pharmacol Exp Ther 358, 371-386, (2016)). One of these AAK1 inhibitors recently completed phase 2 clinical trial for diabetic neuropathic pain with promising results (Busui, R. et al. Diabetes 72, (2023)). Given their excellent safety and pharmacokinetics profiles, the AAK1 inhibitors were repurposed to improve taxane response in ovarian cancer. Indeed, with a range of concentrations that do not impact cell viability by themselves, four different small molecular AAK1 inhibitors (500 nM-2 mM) robustly sensitized taxane treatment in ovarian cancer cells in vitro (FIGS.9A). Importantly, the taxane-sensitizing effect was largely blunted in AAK1 knockdown cells (FIG.9B), demonstrating an on-target effect of AAK1 inhibitor. Further studies found that AAK1 inhibitor robustly sensitizes taxane treatment in a panel of ovarian cancer patient-derived organoids, primary cancer cells, and cells lines, including taxane- resistant sublines (FIG.9C), indicating targeting AAK1 improves taxane response in first-line setting and can be used for chemotherapy recurred patients. In vivo studies also demonstrated that AAK1 inhibitor significantly improve taxane response in ovarian cancer cell line and patient-derived xenograft models (FIGS.9D-9E). In addition, TCGA analysis ovarian carcinoma showed AAK1 levels are significantly elevated compared to adjacent normal tissue, demonstrating a therapeutic window for targeting AAK1 in the tumor (FIG.10). Collectively, these results provide evidence for further administering AAK1 inhibitor / taxane combination to subjects with ovarian cancer. To evaluate the efficacy of administering AAK1 inhibitor in combination with a taxane, various clinically relevant ovarian cancer models were established, including a large panel of ovarian cancer cell lines, two patient-derived ovarian cancer primary cells, three patient-derived organoids, three patient-derived xenografts and a ovarian cancer syngeneic model (HGS2) derived from Brca2− / −;Trp53− / −;Pten− / −GEMM mice (Maniati, E. et al. Cell Rep 30, 525-540 e527, (2020)). TheAAK1 inhibitor / taxane combination will be evaluated in vitro using a collection of ovarian cancer cell lines, primary patient tumor cells and patient-derived organoids in vitro. Two of the most clinically advanced AAK1 inhibitors (LX9211 and LP935509) will be further tested in combination with paclitaxel IC50, apoptosis, and cell cycle using a panel of ovarian cancer cell lines, primary patient tumor cells and patient-derived organoids (FIG.3 Attorney’s Docket No.: 21105.0098P1 and FIG.11). The levels of p-AAK, 1-767, total AAK1, p-CDK1, p-Histone H3, and cleaved- caspase 3 will also be assessed by WB, to examine whether AAK1 pT389 level can predict the efficacy of the AAK1 / taxane combination. It will be determined whether the combination is effective in any subtypes of ovarian cancer (e.g., HGSOC, LGSOC, OCCC). The AAK1 inhibitor / taxane combination will be evaluated in vivo using patient- derived xenograft models. Previous in vivo studies showed 30 mg / kg / day of AAK1 inhibitor LP935509 can inhibit AAK1 activity in vivo and this dosage is well-tolerated in mice (Kostich, W. et al. J Pharmacol Exp Ther 358, 371-386 (2016)). As described herein, in vivo cell line xenograft and patient-derived xenograft studies also showed that 30 mg / kg / day of LP935509 enhanced taxane efficacy in vivo without systemic toxicity (FIG.12). Thus, 30 mg / kg / day of LP935509 or LX9211 will be used for additional PDX experiments. PDX tumors will be implanted in the flank of NSG mice (6-week-old, female, 10 group / mice). When tumor sizes reach 150 mm3, the mice will receive vehicle control, single treatment, or combinations as follows: paclitaxel: 20 mg / kg, once / week, i.p.; AAK1 inhibitor 30 mg / kg, daily, i.p. Tumor sizes will be monitored every 3 days. At endpoint, levels of p-AAK1, p- CDK1, p-Histone H3, and cleaved-caspase 3 levels in tumors will be determined by western blot / IHC. AAK1 activity will also be determined by in vitro kinase assay to confirm the effectiveness of inhibitors. The AAK1 inhibitor / taxane combination will be evaluated in vivo using HGS2 syngeneic model derived from Brca2− / −;Trp53− / −;Pten− / −GEMM mice. In addition to their well-described anti-tubulin effect, taxanes recently have been found to induce cancer cell killing through modulating T cell cytotoxicity (Vennin, C. et al. Cancer Cell 41, 1170- 1185.e1112 (2023)). As the human cell line / PDX models do not provide intact immune tumor microenvironment, the AAK1 inhibitor / paclitaxel combination will be tested using a luciferase-expressing, mouse ovarian cancer cell line HGS2 derived from Brca2− / −; Trp53− / −; Pten− / −GEMM mice (Maniati, E. et al. Cell Rep 30, 525-540 e527, (2020)).5x105cells of HGS2 cells will be orthotopically injected in the peritoneal cavity of C57BL / 6 mice (6-week- old, female, 10 mice / group), and randomized into 4 groups. Tumor growth will be monitored by bioluminescence and treatment will be started once tumor signal can be detected (about 40-45 days). At endpoint, various analysis will be similarly performed as in PDX experiment. AAK1 pT389 will be validated as a companion biomarker for the AAK1 inhibitor / taxane combination. A robust companion biomarker predictive of treatment response is important for patient selection and better patient care. The results show that the cell lines that robustly Attorney’s Docket No.: 21105.0098P1 respond to the AAK1 inhibitor / taxane combination (such as PEO1 and OVCAR8) tend to have high level of pT389 phosphorylation compared to cell lines that moderately respond to the combination treatment (OCC1 and OVCAR4), indicating AAK1 pT389 can serve as a companion predictive biomarker for the AAK1 inhibitor / taxane combination. Thus, AAK1 pT389 and 1-767 antibodies will be used, and CyTOF-based single cell profiling will be performed on pre- and post-treatment samples using the PDO and PDX models (Taverna, J. A. et al. Cancer Res 80, 1551-1563 (2020)), in order to validate whether levels of AAK1 pT389 and / or 1-767 can be used as companion biomarkers for prediction of the responsiveness to the combination treatment. In sum, it is expected that the AAK1 inhibitor / taxane combination will synergistically attenuate cell viability in vitro and tumor growth in vivo. The in vitro data showed that for ovarian cancer cell lines and primary tumor cells, 1 mm of LX9211 or LP935509 effectively inhibits AAK1 activity but itself induce no cell death. To determine the minimal dose that effectively inhibits AAK1 activity, in vivo experiment will be performed using AAK1 kinase assay and p-AP2 level. Body weight and hematopoietic abnormality in vivo will be monitored. AAK1 activity in inhibitor-treated tumor samples will also be examined to confirm on-target effects. Statistical Analyses. Two-sample t-test will be used to compare tumor mass at the endpoint between each experimental and control group. A mixed model will be used in each set to compare the tumor growth across 4 groups as well as for pairwise comparisons when a significant overall difference exists. An interaction term between AAK1 inhibitor and paclitaxel will be added in the mixed model to test synergistic effect on the tumor growth. Statistical Power. The ratio of the tumor mass between control and experimental group is assumed to be more than 1.5. A sample size of 10 mice per group will achieve at least 80% power at the significance level of 0.05 to detect a difference of 1.5 times in tumor mass between control and experimental group, assuming the coefficient of variation on the original scale is 0.3.

Claims

Attorney’s Docket No.: 21105.0098P1 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject, the method comprising: administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid.

2. The method of claim 1, wherein the taxane or the vinca alkaloid is administered prior to, concurrently or sequentially with the therapeutically effective amount the AAK1 inhibitor.

3. The method of any one of claims 1-2, wherein the subject exhibits intrinsic or an acquired resistance to the taxane or the vinca alkaloid.

4. The method of any one of claims 1-3, wherein the cancer is ovarian cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma.

5. The method of any one of claims 1-4, wherein the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane.

6. The method of any one of claims 1-4, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, vinflunine, or vindesine.

7. The method of any one of claims 1-6, wherein the therapeutically effective amount the taxane or the vinca alkaloid is administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.Attorney’s Docket No.: 21105.0098P1 8. The method of any one of claims 1-7, wherein the taxane or the vinca alkaloid is administered at a dose that is 1 to 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

9. The method of any one of claims 1-8, wherein the AAK1 inhibitor is LX9211, LP935509, LP922761, or SGC-AAK1-1.

10. The method of any one of claims 1-9, wherein the cancer is associated with elevated levels of AP2 associated kinase 1 (AAK1) prior to the administration of the AAK1 inhibitor.

11. A method of enhancing the responsiveness of a cancer cell to a taxane or a vinca alkaloid, the method comprising contacting the cancer cell with a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) and a therapeutically effective amount of a taxane or the vinca alkaloid.

12. The method of claim 11, wherein the therapeutically effective amount of the taxane or the vinca alkaloid is administered prior to, concurrently or sequentially administering the therapeutically effective amount the AAK1 inhibitor.

13. The method of any one of claims 11-12, wherein the cancer cell was resistant to the taxane or the vinca alkaloid prior to the administration of the AAK1 inhibitor.

14. The method of any one of claims 11-13, wherein the cancer cells are human cancer cells.

15. The method of any one of claims 11-14, wherein the cancer cell is in a subject.

16. The method of any one of claims 11-15, wherein the cancer cell is an ovarian cancer cell, a lung cancer cell, a breast cancer, a head and neck cancer cell, a pancreatic cancer cell, a prostate cancer cell, an endometrial cancer cell, a gastric cancer cell, a bladder cancer cell, an anaplastic thyroid cancer cell, a cervical cancer cell, or a melanoma cancer cell.Attorney’s Docket No.: 21105.0098P1 17. The method of any one of claims 11-16, wherein the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane.

18. The method of any one of claims 11-16, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, vinflunine, or vindesine.

19. The method of any one of claims 11-17, wherein the therapeutically effective amount of the taxane or the vinca alkaloid is administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

20. The method of any one of claims 11-19, wherein the taxane or the vinca alkaloid is administered at a dose that is 1 to 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

21. The method of any one of claims 11-20, wherein the AAK1 inhibitor is LX9211, LP935509, LP922761, or SGC-AAK1-1.

22. A method of increasing the efficacy of a taxane or a vinca alkaloid in a subject with cancer, the method comprising: administering to the subject a therapeutically effective amount of an AP2 associated kinase 1 (AAK1) inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid.

23. The method of claim 22, wherein therapeutically effective amount of the taxane or the vinca alkaloid is administered prior to, concurrently or sequentially with the therapeutically effective amount of the AAK1 inhibitor.

24. The method of any one of claims 22-23, wherein the therapeutically effective amount the taxane or the vinca alkaloid is administered at a dose equal to or lower than a recommended dose for the treatment of a cancer using the taxane or the vinca alkaloid alone.Attorney’s Docket No.: 21105.0098P1 25. The method of any one of claims 22-24, wherein the taxane or the vinca alkaloid is administered at a dose that is 1 to 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

26. The method of any one of claims 22-25, wherein the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane.

27. The method of any one of claims 22-25, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, vinflunine, or vindesine.

28. The method of any one of claims 22-26, wherein the AAK1 inhibitor is LX9211, LP935509, LP922761, or SGC-AAK1-1.

29. The method of any one of claims 22-28, wherein the subject exhibits intrinsic or an acquired resistance to the taxane or the vinca alkaloid.

30. The method of any one of claims 22-29, wherein the subject is taxane or the vinca alkaloid naïve.

31. The method any one of claims 22-30, wherein the subject has cancer.

32. The method of claim 31, wherein the cancer is ovarian cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma.

33. The method of any of the preceding claims, further comprising administering chemotherapy or radiation to the subject.

34. The method of claim 33, wherein the chemotherapy is cisplatin, carboplatin, or doxorubicin.

35. The method of any of the preceding claims, wherein the subject is identified as being in need of treatment before the administration step.Attorney’s Docket No.: 21105.0098P1 36. The method of any of the preceding claims, wherein the subject has been identified as having elevated AP2 associated kinase 1 (AAK1) levels.

37. The method of any of any of claims 1 to 36, the subject has been diagnosed with cancer prior to the administering step.

38. The method of any of the preceding claims, wherein the subject is a human.

39. The method of any of the preceding claims, wherein the therapeutically effective amount of the taxane or the vinca alkaloid is administered orally or parentally.

40. The method of any of the preceding claims, wherein the therapeutically effective amount of the AAK1 inhibitor is administered orally or parentally.

41. The method of any one of claims 39-40, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or direct injection.

42. A method comprising: a) obtaining or having obtained a sample comprising tumor cells from a cancer patient; b) determining the level of AP2 associated kinase 1 (AAK1) in the tumor cells of the sample; c) identifying the cancer patient as a suitable candidate for treatment with an AAK1 inhibitor and a taxane or a vinca alkaloid, when the level of AAT1 is higher than a level of AAT1 in a control sample and identifying the cancer patient as an unsuitable candidate for treatment with the AAK1 inhibitor and the taxane or the vinca alkaloid, when the level of AAT1 is the same or lower than a level in a control sample; and d) administering a therapeutically effective amount of an AAK1 inhibitor and a therapeutically effective amount of a taxane or a vinca alkaloid to the cancer patient identified as the suitable candidate, and not administering a therapeutically effective amount of an AAK1 inhibitorAttorney’s Docket No.: 21105.0098P1 and a therapeutically effective amount of a taxane or a vinca alkaloid to the cancer patient identified as the unsuitable candidate.

43. The method of claim 42, wherein the cancer patient has ovarian cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, endometrial cancer, gastric cancer, bladder cancer, anaplastic thyroid cancer, cervical cancer, or melanoma.

44. The method of any of claims 42-43, wherein the sample is a biopsy.

45. The method of any of claims 42-44, wherein the therapeutically effective amount of the AAK1 inhibitor and the therapeutically effective amount of the taxane or the vinca alkaloid are administered orally or parentally.

46. The method of claim 45, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or direct injection.

47. The method of any one of claims 42-46, wherein the therapeutically effective amount of the taxane or the vinca alkaloid is administered at a dose equal to or lower than a recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

48. The method of any one of claims 42-47, wherein the dose is 1 to 5 times lower than the recommended dose for the treatment of cancer using the taxane or the vinca alkaloid alone.

49. The method of any one of claims 42-48, wherein the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane.

50. The method of any one of claims 42-48, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, vinflunine, or vindesine.

51. The method of any one of claims 42-48, wherein the AAK1 inhibitor is LX9211, LP935509, LP922761, or SGC-AAK1-1.Attorney’s Docket No.: 21105.0098P1 52. The method of any of the preceding claims, wherein the taxane is paclitaxel, docetaxel, cabazitaxel, or abraxane.

53. The method of any of the preceding claims, wherein the vinca alkaloid is vinblastine, vinorelbine, vincristine, vinflunine, or vindesine.

54. The method of any of the preceding claims, wherein the AAK1 inhibitor is LX9211, LP935509, LP922761, or SGC-AAK1-1.

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