Application of pharmaceutical composition in cancer treatment

Abstract

The invention discloses an application of a pharmaceutical composition in cancer treatment. The pharmaceutical composition comprises a BCL-XL inhibitor and an HER2 targeting drug or comprises the BCL-XL inhibitor and an STAT3 inhibitor. The invention provides a medical use of a pharmaceutical composition according to the invention for the treatment or prevention of cancer. The invention also provides a method for treating or preventing cancers, provides a brand new treatment scheme for the technical field of cancer treatment, and has important scientific significance and clinical application value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically, relates to an application of a pharmaceutical composition in treating cancer, and more specifically, relates to an application of a BCL-XL inhibitor and a HER2 targeted drug in the preparation of a drug for treating cancer. Background Art

[0002] Cancer is one of the most harmful diseases to human life and health, and a large number of people die from cancer every year. Currently, cancer is usually treated with surgery, radiotherapy, chemotherapy, and drug therapy. However, the effect of surgical treatment alone is poor, and the prognosis is poor for some advanced patients. Therefore, the demand for more effective strategies for cancer has not been met.

[0003] BCL-XL inhibitors are a class of drugs that can inhibit the function of BCL-XL (B-cell lymphoma / leukemia-2 gene long homolog X chromosome) protein. By inhibiting the function of BCL-XL protein, it promotes cell apoptosis and prevents the growth and spread of cancer cells. Recent studies have shown that BCL-XL inhibitors perform well in anti-cancer treatment and have a positive effect on non-Hodgkin's lymphoma and diabetic macular edema.

[0004] HER2 targeted drugs are therapeutic drugs for HER2 (human epidermal growth factor receptor 2) positive cancers. They inhibit HER2-mediated cell proliferation, differentiation and other signal transduction by specifically binding to HER2 receptors, thereby inhibiting tumor growth. In clinical treatment, combined use with chemotherapy or radiotherapy can enhance the therapeutic effect. However, there are currently no reports on the combined treatment of cancer with BCL-XL inhibitors and HER2 targeted drugs. Summary of the invention

[0005] In view of this, in order to solve the above-mentioned technical problems currently faced in this field, the purpose of the present invention is to provide a combined pharmaceutical composition for treating cancer, thereby providing an effective drug combination strategy for the treatment of cancer.

[0006] In order to achieve the above object, the present invention adopts the following technical solution: A first aspect of the present invention provides a pharmaceutical composition for preventing and / or treating cancer.

[0007] Furthermore, the pharmaceutical composition comprises a BCL-XL inhibitor and a HER2 targeted drug.

[0008] Furthermore, the BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, the HER2 targeted drug is selected from any one of Trastuzumab or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the cancer includes gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, blood cancer, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, esophageal cancer or neuroblastoma.

[0011] Furthermore, the cancer is selected from gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer.

[0012] Further, when the cancer is gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 31.5nM~500nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL); Further, when the cancer is breast cancer, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 12.5nM~200nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL); Further, when the cancer is ovarian cancer, the concentration ratio of A1331852 to Lapatinib is (0.625 μM~10 μM: 0.625 μM~10 μM); the concentration ratio of A1331852 to Neratinib is (0.625 μM~10 μM: 62.5 nM~1000 nM); the concentration ratio of A1331852 to Trastuzumab is (0.625 μM~10 μM: 12.5 ng / mL~200 ng / mL); Furthermore, when the cancer is bladder cancer, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 12.5nM~200nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL).

[0013] Furthermore, when the cancer is gastroesophageal adenocarcinoma, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 62.5 nM~1000 nM); the concentration ratio of ABT263 to Neratinib is (0.04 μM~10 μM: 31.5 nM~500 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); Furthermore, when the cancer is breast cancer, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 62.5 nM~1000 nM); the concentration ratio of ABT263 to Neratinib is 0.04 μM~10 μM: 31.5 nM~500 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); Furthermore, when the cancer is ovarian cancer, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 0.625 μM~10 μM); the concentration ratio of ABT263 to Neratinib is (0.04 μM~10 μM: 12.5 nM~200 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); Furthermore, when the cancer is bladder cancer, the concentration ratio of ABT263 to Lapatinib is (0.04μM~10μM: 62.5nM~1000nM); the concentration ratio of ABT263 to Neratinib is (0.04μM~10μM: 12.5nM~200nM); the concentration ratio of ABT263 to Trastuzumab is (0.04μM~10μM: 12.5ng / mL~200ng / mL).

[0014] In a specific embodiment of the present invention, the inventors of the present invention discovered for the first time that the combination of BCL-XL inhibitors and HER2 targeted drugs has a synergistic effect in the treatment of various cancers including gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, etc. The present invention has proved through experiments that the combination of the two can significantly inhibit the growth of cancer cells, showing a significant synergistic killing effect.

[0015] In some embodiments, the BCL-XL inhibitor comprises any agent capable of inhibiting BCL-XL, illustratively, the BCL-XL inhibitor includes but is not limited to A1331852, ABT263, BH3I-, A1155463, WEHI-539 hydrochloride. In a specific embodiment of the present invention, the BCL-XL inhibitor is selected from A1331852 and ABT263.

[0016] In some embodiments, the HER2 targeted drug includes any agent capable of inhibiting HER2, and illustratively, the HER2 targeted drug includes but is not limited to: Lapatinib, Neratinib, Trastuzumab, Pertuzumab, T-DM1, DS-B201, Neratinib, Pyrotinib. In a specific embodiment of the present invention, the HER2 targeted drug is selected from Lapatinib, Neratinib, and Trastuzumab.

[0017] In some embodiments, the pharmaceutically acceptable salt refers to an acid salt formed with an inorganic and / or organic acid and a basic salt formed with an inorganic and / or organic base. In addition, when the compound contains a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), a zwitterion may be formed and the zwitterion is included in the pharmaceutically acceptable salts described herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful. A pharmaceutically acceptable salt of the compound can be formed, for example, by reacting the compound with an amount of an acid or a base in a medium, such as a medium in which the salt is precipitated or an aqueous medium (freeze-dried after the reaction).

[0018] Specific pharmaceutically acceptable salts include those salts which are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and which are commensurate with a reasonable benefit or risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts (pharmaceutically acceptable salts) are well known in the art. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases.

[0019] The example of pharmaceutically acceptable nontoxic acid addition salt is the salt formed with inorganic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or the salt formed with organic acid, for example acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also include the salt formed using the conventional methods in the art, for example, ion exchange method.Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, hemisulfate, enanthate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate. Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts and the like.

[0020] In the present invention, the prevention and / or treatment refers to delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of the symptoms that will develop or are expected to develop. Therefore, these terms include improving existing disease symptoms, preventing additional symptoms, improving or preventing potential metabolic causes of symptoms, inhibiting a disorder or disease, for example, preventing the development of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, alleviating a condition caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0021] Furthermore, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0022] In some embodiments, the pharmaceutically acceptable carriers and / or excipients include, but are not limited to, diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers, and disintegrants.

[0023] In some embodiments, the diluent includes, but is not limited to, lactose, sodium chloride, glucose, urea, starch, water, and the like.

[0024] In some embodiments, the binder includes but is not limited to starch, pregelatinized starch, dextrin, maltodextrin, sucrose, gum arabic, gelatin, methyl cellulose, carboxymethyl cellulose, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, alginic acid and alginate, xanthan gum, hydroxypropyl cellulose and hydroxypropyl methylcellulose, etc.

[0025] In some embodiments, the surfactant includes, but is not limited to, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, cetyl alcohol, and the like.

[0026] In some embodiments, the humectant includes but is not limited to glycerol, starch, and the like.

[0027] In some embodiments, the adsorption carrier includes, but is not limited to, starch, lactose, bentonite, silica gel, kaolin, and bentonite.

[0028] In some embodiments, the lubricant includes but is not limited to: zinc stearate, glyceryl monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, monolauric sucrose ester, sodium lauryl sulfate, magnesium lauryl sulfate, magnesium dodecyl sulfate, etc.

[0029] In some embodiments, the filler includes but is not limited to: mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polymeric sugars, coupling sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, laminarin powder, agar powder, calcium carbonate, sodium bicarbonate, etc.

[0030] In some embodiments, the disintegrant includes but is not limited to: cross-linked vinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl methyl, cross-linked sodium carboxymethyl cellulose, soybean polysaccharide, etc.

[0031] In some embodiments, the pharmaceutically acceptable carrier and / or excipient is used to help the stability of the formulation or to help improve its activity or its biological effectiveness or to produce an acceptable taste or smell in the case of oral administration as needed. The pharmaceutical composition thus prepared can be administered by any appropriate administration method known to those skilled in the art as needed. When the pharmaceutical composition is used, a safe and effective amount of the pharmaceutical composition of the present invention is administered to a human.

[0032] In some embodiments, the suitable dosage of the pharmaceutical composition described in the present invention can be prescribed in a variety of ways according to factors such as formulation method, administration method, patient's age, weight, gender, morbidity, diet, administration time, administration route, excretion rate and reaction sensitivity. A skilled physician can usually easily determine the prescription and the desired dosage that is effective for treatment.

[0033] Furthermore, the pharmaceutical composition of the present invention may also include additives such as stabilizers, bactericides, buffers, isotonic agents, chelating agents, pH control agents and surfactants.

[0034] Further, the pharmaceutical composition described in the present invention can also be used in combination with other drugs for treating cancer, and other therapeutic compounds can be administered simultaneously with the main active ingredient, or even administered simultaneously in the same composition. Other therapeutic compounds can also be administered separately in a separate composition or in a dosage form different from the main active ingredient. Partial doses of the main ingredient can be administered simultaneously with other therapeutic compounds, while other doses can be administered separately. During the treatment process, the dosage of the pharmaceutical composition of the present invention can be adjusted according to the severity of the symptoms, the frequency of recurrence, and the physiological response of the treatment regimen.

[0035] Furthermore, the dosage form of the pharmaceutical composition includes a parenteral dosage form and / or a parenteral dosage form.

[0036] Furthermore, the non-intestinal administration dosage form includes an injection dosage form, a cavity administration dosage form, a mucosal administration dosage form and / or a skin administration dosage form.

[0037] Furthermore, the dosage forms for administration via the gastrointestinal tract include tablets, granules, capsules, solutions, powders, sustained-release preparations, emulsions, suspensions, syrups and / or drops.

[0038] In some embodiments, the dosage form of the pharmaceutical composition of the present invention is a dosage form that is prepared by conventional methods and is conducive to administration, including but not limited to: parenteral dosage forms, gastrointestinal dosage forms, and specific examples include but are not limited to: aqueous solution injection, powder injection, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder sprays, sustained-release agents and controlled-release agents, etc.

[0039] In some embodiments, the injection dosage forms include, but are not limited to, intravenous injections, intramuscular injections, subcutaneous injections, intradermal injections, intracavity injections and other injections.

[0040] In some embodiments, the cavity administration dosage form includes, but is not limited to, suppositories, aerosols, effervescent tablets, drops, pills, etc., and is used in the rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0041] In some embodiments, the mucosal administration dosage form includes, but is not limited to, eye drops, nasal drops, eye ointments, gargles, sublingual tablets, adhesive tablets, patches, and the like.

[0042] In some embodiments, the skin administration dosage form includes, but is not limited to, topical solutions, lotions, liniments, ointments, plasters, pastes, patches, and the like.

[0043] In some embodiments, the pharmaceutical composition contains pharmaceutical excipients, which can be conventionally used in various preparations, including but not limited to isotonic agents, buffers, flavoring agents, excipients, fillers, adhesives, disintegrants and lubricants, etc.; or selected for use in order to adapt to the substance, including but not limited to emulsifiers, solubilizers, antibacterial agents, analgesics and antioxidants, etc. Such excipients can effectively improve the stability and solubility of the active ingredients contained in the composition or change the release rate and absorption rate of the active ingredients, thereby improving the metabolism of various active ingredients in the body, thereby enhancing the administration effect of the composition. In addition, excipients used to achieve specific administration purposes or methods, such as sustained-release administration, controlled-release administration and pulse administration, etc., include but are not limited to gelatin, albumin, chitosan, polyether and polyester polymer materials (for example: polyethylene glycol, polyurethane, polycarbonate and its copolymers, etc.). The main manifestations of the drug administration are: improving the therapeutic effect, improving the bioavailability, reducing toxic side effects and improving patient compliance, etc.

[0044] In some embodiments, the pharmaceutical composition or pharmaceutical preparation may also contain other drugs or agents that can be used for treatment and / or prevention, or auxiliary treatment and / or prevention. The other drugs or agents are not particularly limited. As long as they can produce the expected treatment and / or prevention, or auxiliary treatment and / or prevention effect on cancer, they are within the scope of protection of the present invention.

[0045] In some embodiments, the other drugs or agents that can be used for treatment and / or prevention, or adjuvant treatment and / or prevention include but are not limited to: chemotherapy drugs, specifically, the chemotherapy drugs include but are not limited to: taxane drugs (paclitaxel, docetaxel, cabazitaxel), antibiotic drugs (doxorubicin, epirubicin, daunorubicin, pirarubicin, etoposide, irinotecan, mitoxantrone), antimetabolites (cisplatin, carboplatin, lobaplatin, nedaplatin, oxaliplatin, gemcitabine, 5-fluorouracil), alkylating agents (cyclophosphamide, ifosfamide).

[0046] Furthermore, the pharmaceutical composition is a single compound preparation or a combination of two separate single preparations.

[0047] Furthermore, the compound preparation is a compound preparation comprising a BCL-XL inhibitor and a HER2 targeted drug.

[0048] Furthermore, the combination of single preparations is a combination of a single preparation comprising a BCL-XL inhibitor and a single preparation comprising a HER2 targeted drug.

[0049] Furthermore, the BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof.

[0050] Furthermore, the HER2 targeted drug is selected from any one of Trastuzumab or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the compound preparation refers to a preparation made of two or more active pharmaceutical ingredients. For example, when the pharmaceutical composition of the present invention is a compound preparation, it may mean that it contains both a BCL-XL inhibitor and a HER2 targeted drug.

[0052] In some embodiments, the single-ingredient preparation refers to a preparation made of a single active pharmaceutical ingredient. For example, when the pharmaceutical composition of the present invention is a combination of single-ingredient preparations, it may represent a combination of a single-ingredient preparation containing a BCL-XL inhibitor and a single-ingredient preparation containing a HER2 targeted drug.

[0053] In some embodiments, the HER2 targeted drug and the BCL-XL inhibitor in the pharmaceutical composition can be administered simultaneously, separately or successively. Wherein, simultaneously refers to the synchronous administration of two drugs. If not administered simultaneously, then administered successively within a time range, so that the two can act therapeutically within the same time range. Therefore, sequential administration allows administration of another drug within 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours or several hours after providing a drug, provided that the circulation half-life of the first administered drug allows both to exist simultaneously in therapeutically effective amounts. The time delay of administration between each component will change according to the exact nature of the components, the interactions therebetween, and their respective half-lives. Different from simultaneously or successively, respectively refers to the significant interval between the administration of one drug and another drug, that is, when the second drug is administered, the first administered drug may no longer be present in the bloodstream in a therapeutically effective amount.

[0054] A second aspect of the present invention provides a pharmaceutical composition for preventing and / or treating gastroesophageal adenocarcinoma.

[0055] Furthermore, the pharmaceutical composition comprises a BCL-XL inhibitor and a STAT3 inhibitor.

[0056] Preferably, the BCL-XL inhibitor is selected from A1331852 or a pharmaceutically acceptable salt thereof; and the STAT3 inhibitor is selected from Napabucasin or a pharmaceutically acceptable salt thereof.

[0057] Preferably, when phosphorylated STAT3 is highly expressed in the gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Napabucasin is (0.002 μM-10 μM: 80 nM-300 nM).

[0058] Preferably, when phosphorylated STAT3 is lowly expressed in the gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Napabucasin is (25nM-400nM: 50nM-1000nM).

[0059] The third aspect of the present invention provides an in vitro method for inhibiting cancer cells or promoting apoptosis of cancer cells for non-therapeutic purposes.

[0060] Furthermore, the method comprises: treating cancer cells with the pharmaceutical composition described in the first aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention.

[0061] Furthermore, the cancer cells include gastroesophageal adenocarcinoma cells, adenocarcinoma cells, ovarian cancer cells, bladder cancer cells, lung cancer cells, colon cancer cells, rectal cancer cells, prostate cancer cells, blood cancer cells, lymphoma cells, cervical cancer cells, osteosarcoma cells, glioblastoma cells, melanoma cells, pancreatic cancer cells, liver cancer cells, renal cancer cells, gallbladder cancer cells, bile duct cancer cells or neuroblastoma cells.

[0062] Furthermore, the cancer is selected from gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells.

[0063] In a specific embodiment of the present invention, the present invention has experimentally demonstrated that the pharmaceutical composition has a significant synergistic inhibitory effect on the growth and proliferation of gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells. Therefore, the pharmaceutical composition can be used as an inhibitor for inhibiting the growth and proliferation of gastroesophageal cancer cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells for non-therapeutic purposes, and can be used in the field of scientific research, such as more in-depth research on the growth and metabolic mechanisms or behaviors of gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells, and screening for potential drugs that can be used to treat gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells.

[0064] The present invention also provides a method for treating and / or preventing cancer, the method comprising: administering a therapeutically and / or preventively effective amount of the pharmaceutical composition according to the first aspect of the present invention to a subject in need thereof.

[0065] Furthermore, the cancer includes gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, blood cancer, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer or neuroblastoma.

[0066] Furthermore, the cancer is selected from gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer.

[0067] In the present invention, the subject includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, etc. In one embodiment of the present invention, the subject is a human. The term subject includes confirmed patients.

[0068] In the present invention, the effective amount refers to the amount of the compound that effectively produces the desired preventive, alleviating or therapeutic effect. Depending on the compound, the symptom and its severity, the age of the treated mammal and other factors, the amount of the pharmaceutical composition of the present invention to achieve the effective amount will also vary accordingly, but the specific amount can be routinely determined by a person of ordinary skill in the art based on the knowledge in the art mastered by him / her and the content disclosed in the present invention, and the dosage that can produce the above-mentioned effects is within the scope of protection of the present invention.

[0069] In some embodiments, the administration of the pharmaceutical composition can be carried out in any form, including but not limited to: oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), oral and / or suppository administration, and other administration routes. In one embodiment of the invention, the active compound or compound combination as described above is provided in a solid dosage form known in the art. The most effective dosage form will depend on the bioavailability or pharmacokinetics of the selected specific agent and the severity of the patient's disease. Oral dosage forms are particularly preferred because they are easy to use and expected favorable patient compliance.

[0070] In some embodiments, the pharmaceutical composition or pharmaceutical preparation may be administered to the subject by oral administration, injection or topical administration. For example, the method may include administering the pharmaceutical composition or pharmaceutical preparation to the subject three times a day, once a day, once every two days, etc. In some embodiments, injection administration may include subcutaneous injection, intramuscular injection, intravenous injection, etc. In some embodiments, injection administration may include injecting the pharmaceutical composition directly into the lesion or in an area near the lesion. In some embodiments, a combination of different administration methods may be used.

[0071] A fourth aspect of the present invention provides any of the following applications.

[0072] Furthermore, the application includes: (1) Use of a combination of a BCL-XL inhibitor and a HER2-targeted drug in the preparation of a drug for the prevention and / or treatment of cancer; (2) The combined use of BCL-XL inhibitors and HER2-targeted drugs to inhibit cancer cells or promote apoptosis of cancer cells for non-therapeutic purposes in vitro; (3) Use of a combination of a BCL-XL inhibitor and a HER2-targeted drug in the preparation of a reagent for inhibiting cancer cells or cancer cell apoptosis in vitro; (4) Use of BCL-XL inhibitors in the preparation of drugs for improving the therapeutic effect of HER2-targeted drugs in treating cancer; (5) Use of HER2-targeted drugs in the preparation of drugs for improving the therapeutic effect of BCL-XL inhibitors in treating cancer; (6) Use of a BCL-XL inhibitor and a STAT3 inhibitor in combination for the preparation of a drug for preventing and / or treating gastroesophageal adenocarcinoma; (7) The combined use of BCL-XL inhibitors and STAT3 inhibitors to inhibit gastroesophageal adenocarcinoma cells or promote apoptosis of gastroesophageal adenocarcinoma cells for non-therapeutic purposes in vitro; (8) Use of a BCL-XL inhibitor and a STAT3 inhibitor in combination for the preparation of a reagent for inhibiting apoptosis of gastroesophageal adenocarcinoma cells or gastroesophageal carcinoma cells in vitro; (9) Use of BCL-XL inhibitors in the preparation of drugs for improving the therapeutic effect of STAT3 inhibitors in the treatment of gastroesophageal adenocarcinoma; (10) Use of a STAT3 inhibitor in the preparation of a drug for improving the therapeutic effect of a BCL-XL inhibitor in the treatment of gastroesophageal adenocarcinoma.

[0073] Furthermore, the BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof.

[0074] Furthermore, the HER2 targeted drug is selected from any one of Lapatinib or a pharmaceutically acceptable salt thereof, Trastuzumab or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof.

[0075] Furthermore, the STAT3 inhibitor is selected from Napabucasin or a pharmaceutically acceptable salt thereof.

[0076] Furthermore, the cancer includes gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, blood cancer, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, esophageal cancer or neuroblastoma.

[0077] Furthermore, the cancer is selected from gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer.

[0078] The present invention has the beneficial effects: The present invention first discovered that the combination of BCL-XL inhibitors and HER2 targeted drugs has a synergistic effect on the treatment of gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer, and discovered that the combination of BCL-XL inhibitors and STAT3 inhibitors also has a synergistic effect on the treatment of gastroesophageal adenocarcinoma. The combined treatment method can significantly improve the therapeutic effect of gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer, and achieve better anti-tumor efficacy. The present invention provides a new treatment plan for the technical field of gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, and bladder cancer treatment, which has important scientific significance and clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 Show the effect of BCL-XL inhibitor combined with HER2 targeted drugs on the activity of gastroesophageal adenocarcinoma cells; Figure 2 Show the effect of BCL-XL inhibitors combined with HER2-targeted drugs on breast cancer cell activity; Figure 3 Show the effect of BCL-XL inhibitors combined with HER2-targeted drugs on the activity of ovarian cancer cells; Figure 4 Show the effect of BCL-XL inhibitors combined with HER2-targeted drugs on the activity of bladder cancer cells; Figure 5 Shows the effect of BCL-XL inhibitor combined with STAT3 inhibitor on the activity of gastroesophageal adenocarcinoma cells. DETAILED DESCRIPTION

[0080] Example 1 Effect of BCL-XL inhibitor combined with HER2 targeted drug on cancer cell activity 1. Experimental methods (1) Cell plating The drug sensitivity test was carried out using tumor cells in the logarithmic growth phase. The gastroesophageal adenocarcinoma cell line NCI-N87, breast cancer cell line HCC1954, ovarian cancer cell line SKOV3 and bladder cancer cell line T24 were used in the experiment. The cells were digested with trypsin-EDTA cell digestion solution and counted. 3000 cells / 50μL / well were evenly plated into 96-well plates using a multi-channel pipette and placed at 37°C with 5% CO 2 The thermostatic incubator was set aside. To reduce the edge effect, the outermost edge wells of the 96-well plate were not used for the experiment and were filled with sterile PBS to reduce the effect of culture medium evaporation on cell growth and ensure the stability of the experiment.

[0081] (2) Drug preparation Drug concentration gradient design: Drug A: HER2 targeted drugs, including Trastuzumab, Lapatinib and Neratinib used in this project; Drug B: BCL-XL inhibitors. A1331852 and ABT263 were used in this project. Negative control: Trastuzumab solvent is PBS, and other drug solvents are DMSO. PBS or DMSO was used as negative control in the implementation of this project; Drug A and A1331852: Use 4 times the actual application concentration to prepare the highest concentration, and dilute it in 1 / 2 gradient to prepare 5 concentrations; ABT-263: Use 4 times the actual application concentration to prepare the highest concentration, and dilute it in a 1 / 4 gradient to prepare 5 concentrations; Negative control: Add PBS or DMSO in a volume corresponding to the highest drug concentration as a negative control.

[0082] Use a 1.8 mL 96-well plate to perform gradient dilutions of the above drugs for later use.

[0083] (3) Drug treatment Use a multichannel pipette to treat the cells plated in step (1) with the drug prepared in step (2).

[0084] Direction of increasing concentration of drug A: set to horizontal (row direction), 6 gradient concentrations, marked as C A (1-6); Drug B concentration increasing direction: set to vertical (column direction), 6 titer concentrations, marked as C B (1-6).

[0085] The settings of the 96-well plate are shown in Table 1: Table 1 Drug concentration settings

[0086] The cell activity was detected after treatment with BCLXL inhibitors combined with Trastuzumab for 96 hours, and the cell activity was detected after treatment with BCLXL inhibitors combined with Lapatinib or Neratinib for 72 hours.

[0087] (4) Cell activity detection In this project, the Promega CellTiter-Glo® Luminescent Cell Viability Assay Kit was used to detect cell activity. The specific operation is as follows: A. After taking the culture plate out of the incubator, place it at room temperature for 10 minutes to allow it to equilibrate to room temperature.

[0088] B. Use a multichannel pipette to add 40 μL of CellTiter-Glo reagent / well and shake on a horizontal shaker at low speed (100–200 rpm) for 10 minutes. C. Use MD multi-function fluorescence microplate reader to measure the fluorescence intensity, set the reading parameters in integration mode, and set the acquisition time of fluorescence or luminescence signal to 1000 milliseconds (1 second) to ensure signal stability.

[0089] (5) Data analysis 5.1 Calculate the percentage of cell viability: Cell activity percentage = luminescence signal of drug-treated cells / luminescence signal of negative control cells × 100% 5.2 Calculate the synergy score of the drug combination: This project uses the Bliss independence model to evaluate the synergistic effect of the combination of drug A and drug B.

[0090] First, calculate the inhibition rate of drug on cell growth, inhibition rate = 1-cell activity percentage; The predicted value of the cell growth inhibition rate of the combination of two drugs = (inhibition rate of drug A + inhibition rate of drug B - inhibition rate of drug A × inhibition rate of drug B) × 100% Bliss synergy score = observed value of cell growth inhibition rate of two drugs combined - predicted value of cell growth inhibition rate of two drugs combined If the Bliss synergy score > 0, it indicates a synergistic effect; if the Bliss synergy score = 0, it indicates an additive effect; if the Bliss synergy score < 0, it indicates an antagonistic effect.

[0091] 2. Experimental results (1) Figure 1-5 The heat map of cell activity percentage and Bliss synergy score of BCL-XL inhibitor combined with HER2 targeted drugs in gastroesophageal adenocarcinoma, esophageal adenocarcinoma, breast cancer, ovarian cancer and bladder cancer are shown. The specific description is as follows: Vertical axis: represents the increasing concentration of drug A (A1331852 or ABT263); Horizontal axis: represents the increasing concentration of drug B (Trastuzumab, Lapatinib, or Neratinib); Cell activity percentage heat map white to red: indicates that the cell activity percentage decreases from 100 to 0.

[0092] Bliss synergy score heat map: blue indicates Bliss synergy score <0, antagonistic effect, white indicates Bliss synergy score = 0, additive effect; red indicates Bliss synergy score > 0, synergistic effect.

[0093] The experimental results showed that BCL-XL inhibitors and HER2 targeted drugs had significant synergistic effects: the combination of A1331852 and HER2 targeted drugs showed strong synergistic effects in all different types of tumor cells; the combination of ABT263 and HER2 targeted drugs showed strong synergistic effects in gastroesophageal adenocarcinoma, esophageal adenocarcinoma, breast cancer and bladder cancer, and ABT263 and Lapatinib or Neratinib showed strong synergistic effects in ovarian cancer.

[0094] Example 2 Effects of BCL-XL inhibitor combined with STAT3 inhibitor on the activity of gastroesophageal adenocarcinoma cells 1. Experimental methods (1) Cell plating The drug sensitivity test was performed using tumor cells in the logarithmic growth phase. In the experiment, the gastric adenocarcinoma cell lines were divided into two groups: the first group was the phosphorylated STAT3 high-expressing cell lines HGC-27, MKN-45 and AGS, and the second group was the phosphorylated STAT3 low-expressing cell lines SNU-216, NCI-N87 and GCIY. The cells were digested and counted using trypsin-EDTA cell digestion solution, and 3000 cells / 50μL / well were evenly plated into a 96-well plate using a multi-channel pipette and placed at 37°C, 5% CO 2 The thermostatic incubator was set aside. To reduce the edge effect, the outermost edge wells of the 96-well plate were not used for the experiment and were filled with sterile PBS to reduce the effect of culture medium evaporation on cell growth and ensure the stability of the experiment.

[0095] (2) Drug preparation Drug concentration gradient design: Drug A: STAT3 inhibitor, Napabucasin (BBI608) was used in this project; Drug B: BCL-XL inhibitor, A1331852 was used in the implementation of this project; Negative control: The drug solvent is DMSO, and DMSO is used as a negative control in the implementation of this part of the project; Drug A: In experiments on phosphorylated STAT3 high-expressing cell lines HGC-27, MKN-45 and AGS, a dosage of 4 times the actual concentration was used to prepare the highest concentration, and two concentrations were prepared according to a 4 / 5 gradient dilution; in experiments on phosphorylated STAT3 low-expressing cell lines SNU-216, NCI-N87, and GCIY, a dosage of 4 times the actual concentration was used to prepare the highest concentration, and two concentrations were prepared according to a 1 / 2 gradient dilution.

[0096] Drug B: In experiments on phosphorylated STAT3 high-expressing cell lines HGC-27, MKN-45 and AGS, a dosage of 4 times the actual concentration of the drug was used to prepare the highest concentration, and 5 concentrations were prepared according to a 1 / 8 gradient dilution; in experiments on phosphorylated STAT3 low-expressing cell lines SNU-216, NCI-N87 and GCIY, a dosage of 4 times the actual concentration of the drug was used to prepare the highest concentration, and 5 concentrations were prepared according to a 1 / 2 gradient dilution.

[0097] Negative control: Add DMSO at a volume corresponding to the highest drug concentration as a negative control.

[0098] Use a 1.8 mL 96-well plate to perform gradient dilutions of the above drugs for later use.

[0099] (3) Drug treatment Use a multichannel pipette to treat the cells plated in step (1) with the drug prepared in step (2).

[0100] Direction of increasing concentration of drug A: set to horizontal (row direction), 3 gradient concentrations, marked as C A (1-3); Drug B concentration increasing direction: set to vertical (column direction), 6 gradient concentrations, marked as C B (1-6).

[0101] The settings of the 96-well plate are shown in Table 2: Table 2 Drug concentration settings

[0102] The cell activity was detected by combining BCLXL inhibitor and Napabucasin for 72 hours.

[0103] (4) Cell activity detection: The cell activity detection method is as described above.

[0104] 2. Experimental results (1) Figure 5 The heat map of cell activity percentage and Bliss synergy score of BCL-XL inhibitor A1331852 combined with STAT3 inhibitor Napabucasin in phosphorylated STAT3 high-expressing cell lines HGC27, MKN-45, AGS cell lines and phosphorylated STAT3 low-expressing cell lines SNU-216, NCI-N87, GCIY cell lines are shown. The specific instructions are as follows: Vertical axis: represents increasing concentrations of drug A1331852; Horizontal axis: represents the increasing concentration of the drug Napabucasin; Cell activity percentage heat map white to red: indicates that the cell activity percentage decreases from 100 to 0.

[0105] Bliss synergy score heat map: blue indicates Bliss synergy score <0, antagonistic effect, white indicates Bliss synergy score = 0, additive effect; red indicates Bliss synergy score > 0, synergistic effect.

[0106] The experimental results showed that BCL-XL inhibitors and STAT3 inhibitors had significant synergistic effects: the combination of A1331852 and Napabucasin showed strong synergistic effects in the phosphorylated STAT3 high-expressing cell lines HGC27, MKN-45, AGS cell lines and phosphorylated STAT3 low-expressing cell lines SNU-216, GCIY cell lines, and showed an additive effect in the phosphorylated STAT3 low-expressing NCI-N87 cells.

[0107] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A pharmaceutical composition for preventing and / or treating cancer, characterized in that: The pharmaceutical composition comprises a BCL-XL inhibitor and a HER2 targeting drug.

2. The pharmaceutical composition according to claim 1, characterized in that The BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof; The HER2 targeted drug is selected from any one of Trastuzumab or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof; The cancer includes gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, blood cancer, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, esophageal cancer or neuroblastoma; Preferably, the cancer is selected from gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer.

3. The pharmaceutical composition according to claim 2, characterized in that When the cancer is gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 31.5nM~500nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL); When the cancer is breast cancer, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 12.5nM~200nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL); When the cancer is ovarian cancer, the concentration ratio of A1331852 to Lapatinib is (0.625μM ~10μM: 0.625μM ~10μM); the concentration ratio of A1331852 to Neratinib is (0.625μM ~10μM: 62.5nM ~1000nM); the concentration ratio of A1331852 to Trastuzumab is (0.625μM ~10μM: 12.5ng / mL~200ng / mL); When the cancer is bladder cancer, the concentration ratio of A1331852 to Lapatinib is (12.5nM~200nM: 62.5nM~1000nM); the concentration ratio of A1331852 to Neratinib is (12.5nM~200nM: 12.5nM~200nM); the concentration ratio of A1331852 to Trastuzumab is (12.5nM~200nM: 12.5ng / mL~200ng / mL).

4. The pharmaceutical composition according to claim 2, characterized in that When the cancer is gastroesophageal adenocarcinoma, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 62.5 nM~1000 nM); the concentration ratio of ABT263 to Neratinib is (0.04 μM~10 μM: 31.5 nM~500 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); When the cancer is breast cancer, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 62.5 nM~1000 nM); the concentration ratio of ABT263 to Neratinib is 0.04 μM~10 μM: 31.5 nM~500 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); When the cancer is ovarian cancer, the concentration ratio of ABT263 to Lapatinib is (0.04 μM~10 μM: 0.625 μM~10 μM); the concentration ratio of ABT263 to Neratinib is (0.04 μM~10 μM: 12.5 nM~200 nM); the concentration ratio of ABT263 to Trastuzumab is (0.04 μM~10 μM: 12.5 ng / mL~200 ng / mL); When the cancer is bladder cancer, the concentration ratio of ABT263 to Lapatinib is (0.04μM~10μM: 62.5nM~1000nM); the concentration ratio of ABT263 to Neratinib is (0.04μM~10μM: 12.5nM~200nM); the concentration ratio of ABT263 to Trastuzumab is (0.04μM~10μM: 12.5ng / mL~200ng / mL).

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient; Preferably, the dosage form of the pharmaceutical composition includes a parenteral dosage form and / or a parenteral dosage form; Preferably, the parenteral dosage form includes an injection dosage form, a cavity dosage form, a mucosal dosage form and / or a skin dosage form; Preferably, the dosage form for administration via the gastrointestinal tract includes tablets, granules, capsules, solutions, powders, sustained-release preparations, emulsions, suspensions, syrups and / or drops.

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition is a single compound preparation or a combination of two separate single preparations; The compound preparation is a compound preparation comprising a BCL-XL inhibitor and a HER2 targeted drug; The combination of single-ingredient preparations is a combination of a single-ingredient preparation containing a BCL-XL inhibitor and a single-ingredient preparation containing a HER2 targeted drug; The BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof; The HER2 targeted drug is selected from any one of Trastuzumab or a pharmaceutically acceptable salt thereof, Lapatinib or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition for preventing and / or treating gastroesophageal adenocarcinoma, characterized in that: The pharmaceutical composition comprises a BCL-XL inhibitor and a STAT3 inhibitor; Preferably, the BCL-XL inhibitor is selected from A1331852 or a pharmaceutically acceptable salt thereof; the STAT3 inhibitor is selected from Napabucasin or a pharmaceutically acceptable salt thereof; Preferably, when phosphorylated STAT3 is highly expressed in the gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Napabucasin is (0.002 μM-10 μM: 80 nM-300 nM); Preferably, when phosphorylated STAT3 is lowly expressed in the gastroesophageal adenocarcinoma, the concentration ratio of A1331852 to Napabucasin is (25nM-400nM: 50nM-1000nM).

8. An in vitro method for inhibiting cancer cells or promoting apoptosis of cancer cells for non-therapeutic purposes, characterized in that: The method comprises: treating cancer cells with the pharmaceutical composition of any one of claims 1 to 6 or the composition of claim 7; The cancer cells include gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, bladder cancer cells, lung cancer cells, colon cancer cells, rectal cancer cells, prostate cancer cells, blood cancer cells, lymphoma cells, cervical cancer cells, osteosarcoma cells, glioblastoma cells, melanoma cells, pancreatic cancer cells, liver cancer cells, kidney cancer cells, gallbladder cancer cells, bile duct cancer cells, or neuroblastoma cells; Preferably, the cancer is selected from gastroesophageal adenocarcinoma cells, breast cancer cells, ovarian cancer cells, and bladder cancer cells.

9. Any one of the following applications, characterized in that: The applications include: (1) Use of a combination of a BCL-XL inhibitor and a HER2-targeted drug in the preparation of a drug for the prevention and / or treatment of cancer; (2) The combined use of BCL-XL inhibitors and HER2-targeted drugs to inhibit cancer cells or promote apoptosis of cancer cells for non-therapeutic purposes in vitro; (3) Use of a combination of a BCL-XL inhibitor and a HER2-targeted drug in the preparation of a reagent for inhibiting cancer cells or cancer cell apoptosis in vitro; (4) Use of BCL-XL inhibitors in the preparation of drugs for improving the therapeutic effect of HER2-targeted drugs in treating cancer; (5) Use of HER2-targeted drugs in the preparation of drugs for improving the therapeutic effect of BCL-XL inhibitors in treating cancer; (6) Use of a BCL-XL inhibitor and a STAT3 inhibitor in combination for the preparation of a drug for preventing and / or treating gastroesophageal adenocarcinoma; (7) The combined use of BCL-XL inhibitors and STAT3 inhibitors to inhibit gastroesophageal adenocarcinoma cells or promote apoptosis of gastroesophageal adenocarcinoma cells for non-therapeutic purposes in vitro; (8) Use of a BCL-XL inhibitor and a STAT3 inhibitor in combination for the preparation of a reagent for inhibiting apoptosis of gastroesophageal adenocarcinoma cells or gastroesophageal carcinoma cells in vitro; (9) Use of BCL-XL inhibitors in the preparation of drugs for improving the therapeutic effect of STAT3 inhibitors in the treatment of gastroesophageal adenocarcinoma; (10) Use of a STAT3 inhibitor in the preparation of a drug for improving the therapeutic effect of a BCL-XL inhibitor in the treatment of gastroesophageal adenocarcinoma.

10. The use according to claim 9, characterized in that: The BCL-XL inhibitor is selected from any one of A1331852 or a pharmaceutically acceptable salt thereof, ABT263 or a pharmaceutically acceptable salt thereof; The HER2 targeted drug is selected from any one of Lapatinib or a pharmaceutically acceptable salt thereof, Trastuzumab or a pharmaceutically acceptable salt thereof, and Neratinib or a pharmaceutically acceptable salt thereof; The STAT3 inhibitor is selected from Napabucasin or a pharmaceutically acceptable salt thereof; The cancer includes gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer, lung cancer, colon cancer, rectal cancer, prostate cancer, blood cancer, lymphoma, cervical cancer, osteosarcoma, glioblastoma, melanoma, pancreatic cancer, liver cancer, kidney cancer, gallbladder cancer, bile duct cancer, esophageal cancer or neuroblastoma; Preferably, the cancer is selected from gastroesophageal adenocarcinoma, breast cancer, ovarian cancer, bladder cancer.

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