Use of a composition comprising an ERRγ inhibitor as an active ingredient for enhancing anti-cancer effect

Abstract

The present invention relates to a pharmaceutical composition for suppressing resistance to sorafenib in liver cancer and enhancing its anti-cancer effect, which comprises an ERRγ (Estrogen-related receptor γ) inhibitor as an active ingredient. The present invention can be useful as a pharmaceutical composition for treating sorafenib-resistant advanced liver cancer.

Description

Technical Field

[0001] The present invention relates to the use of a composition containing an ERRγ (Estrogen-related receptor γ) inhibitor as an active ingredient for enhancing the anti-cancer effect. More specifically, the present invention provides a pharmaceutical composition containing an ERRγ inhibitor as an active ingredient for suppressing the resistance of liver cancer to sorafenib and enhancing the anti-cancer effect, and a method for treating sorafenib-resistant liver cancer using the same. In addition, the present invention provides a kit for diagnosing sorafenib-resistant liver cancer that utilizes ERRγ as a biomarker for diagnosing sorafenib-resistant liver cancer, and a method for providing information for diagnosing sorafenib-resistant liver cancer using the same.

Background Art

[0002] One of the most common causes of death among Koreans is malignant neoplasm (cancer). According to the statistics of the causes of death announced by the Korean Statistical Office, the liver cancer mortality rate in 2016 was 21.5 per 100,000 population, ranking second among cancer mortality rates after lung cancer mortality rate (Liver Cancer Diagnosis and Treatment Guidelines, Korean Liver Cancer Association, 2018).

[0003] The radical treatment for liver cancer is hepatectomy, which is the primary treatment method for patients with single hepatocellular carcinoma tumors limited to the liver without cirrhosis (Lang H., Liver resection for hepatocellular carcinoma in non-cirrhotic liver without underlying viral hepatitis. Br J Surg. 2005 Feb;92(2):198-202). Even in cases with cirrhosis, if the remaining liver function is expected to be sufficient, it can be preferentially considered (Capussotti L, Muratore A, Massucco P, Ferrero A, Polastri R, Bouzari H Major liver resections for hepatocellular carcinoma on cirrhosis: early and long-term outcomes.. Liver Transpl. 2004 Feb;10(2 Suppl 1):S64-8). However, only 30-40% of those diagnosed early can undergo surgical treatment.

[0004] In cases with extrahepatic metastases such as local lymph nodes and lungs, or hepatic vascular invasion, treatment with sorafenib (Sorafenib, Nexavar (registered trademark)), a multi-kinase inhibitor, will be carried out. However, the degree of improvement in clinical survival does not reach the expected level significantly. Most recur within 6 months, and efforts to overcome this are continuing (Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390).

[0005] On the one hand, cancer metabolism research and new drug development research targeting the metabolic characteristics of cancer are being conducted through research on specific metabolic regulation of cancer cells that are different from normal cells, overcoming the limitations of existing anticancer drugs and targeted therapeutic agents (Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 2011;10:671-684).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] From this, the present inventors confirmed that an inhibitor of ERRγ can suppress the resistance of liver cancer to sorafenib and effectively inhibit the growth of liver cancer, and completed the present invention.

[0008] Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or enhancing the treatment of sorafenib-resistant liver cancer, containing an ERRγ inhibitor as an active ingredient.

[0009] Another object of the present invention is to provide a pharmaceutical composition for suppressing sorafenib resistance of liver cancer, containing an ERRγ inhibitor as an active ingredient.

[0010] Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating liver cancer, containing an ERRγ inhibitor and sorafenib as active ingredients.

[0011] Still another object of the present invention is to provide a method for screening a sorafenib-resistant hepatocellular carcinoma treatment enhancing substance, including a step of treating a candidate substance with sorafenib-resistant hepatocellular carcinoma cells and a step of evaluating the activity or expression of ERRγ in the cells.

[0012] Another object of the present invention is to provide a diagnostic kit for sorafenib-resistant hepatocellular carcinoma, including a preparation for measuring the mRNA level of the ERRγ (Estrogen-related receptor γ) gene or the protein level expressed therefrom.

[0013] Still another object of the present invention is to provide a method for providing information for diagnosing sorafenib-resistant hepatocellular carcinoma, including the following steps: (a) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a hepatocellular carcinoma patient to be confirmed for resistance to sorafenib; (b) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general hepatocellular carcinoma patient who does not have sorafenib-resistant hepatocellular carcinoma; and (c) When the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the hepatocellular carcinoma patient in step (a) as a sorafenib-resistant hepatocellular carcinoma patient.

[0014] Still another object of the present invention is to provide a method for providing information necessary for determining a treatment method for a hepatocellular carcinoma patient, including the following steps: (a) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a hepatocellular carcinoma patient; (b) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general hepatocellular carcinoma patient who does not have sorafenib-resistant hepatocellular carcinoma; and (c) If the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in the step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in the step (b), determining the liver cancer patient in the step (a) as a sorafenib-resistant liver cancer patient.

[0015] Still another object of the present invention is to provide a method for diagnosing and treating sorafenib-resistant liver cancer, comprising the following steps: (a) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient; (b) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who is not sorafenib-resistant liver cancer; and (c) If the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in the step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in the step (b), determining the liver cancer patient in the step (a) as a sorafenib-resistant liver cancer patient, and applying another therapeutic agent for liver cancer other than sorafenib.

[0016] Another object of the present invention is to provide a method for preventing or enhancing the treatment of sorafenib-resistant liver cancer, which comprises administering an ERRγ inhibitor to a patient with sorafenib-resistant liver cancer.

[0017] Still another object of the present invention is to provide a method for suppressing sorafenib resistance in liver cancer, which comprises administering an ERRγ inhibitor to a patient with sorafenib-resistant liver cancer.

[0018] Another object of the present invention is to provide a method for preventing or treating liver cancer, which comprises administering an ERRγ inhibitor and sorafenib to a liver cancer patient.

[0019] However, the technical problems to be achieved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those having ordinary knowledge in the technical field to which the present invention pertains from the following description.

Means for Solving the Problems

[0020] In order to achieve the object of the present invention, the present invention provides a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein or the expression of ERRγ gene for use in the prevention or enhancement of treatment of Sorafenib-resistant liver cancer.

[0021] In connection with this, the present invention provides a pharmaceutical composition for the prevention or enhancement of treatment of Sorafenib-resistant liver cancer, comprising the ERRγ inhibitor as an active ingredient.

[0022] Also, the present invention provides a method for preventing or enhancing the treatment of Sorafenib-resistant liver cancer, comprising the step of administering the ERRγ inhibitor to an individual.

[0023] Furthermore, the present invention provides the use of the ERRγ inhibitor for the prevention, improvement or enhancement of treatment of Sorafenib-resistant liver cancer.

[0024] In one embodiment of the present invention, the preparation for suppressing the activity of the ERRγ protein may be an inverse agonist or antagonist against ERRγ, or an antibody or aptamer capable of specifically binding to ERRγ, but is not limited thereto.

[0025] In one embodiment of the present invention, the inverse agonist against ERRγ may be a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, but is not limited to the above compound as long as it is an ERRγ inverse agonist showing an equivalent effect.

[0026]

Chem.

[0027] In another embodiment of the present invention, the agent for suppressing the expression of the ERRγ gene may be selected from the group consisting of miRNA, siRNA, shRNA, and antisense oligonucleotides that specifically bind to the mRNA of the gene, but is not limited thereto.

[0028] The present invention also provides an agent capable of suppressing the activity of ERRγ protein or the expression of ERRγ gene for use in suppressing the resistance to sorafenib during the prevention or treatment of liver cancer.

[0029] In this regard, the present invention provides a pharmaceutical composition for suppressing sorafenib resistance in liver cancer, comprising the ERRγ inhibitor as an active ingredient.

[0030] Furthermore, the present invention provides a method for suppressing sorafenib resistance in liver cancer, comprising the step of administering the ERRγ inhibitor to an individual.

[0031] In addition, the present invention provides the use of the ERRγ inhibitor for suppressing resistance to sorafenib in liver cancer.

[0032] The present invention also provides an agent capable of suppressing the activity of ERRγ protein or the expression of ERRγ gene for use in the prevention or treatment of liver cancer; and a composition comprising sorafenib.

[0033] In this regard, the present invention provides a pharmaceutical composition for the prevention or treatment of liver cancer, comprising the ERRγ inhibitor; and sorafenib as active ingredients.

[0034] Furthermore, the present invention provides a method for the prevention or treatment of liver cancer, comprising the step of administering to an individual a composition comprising the ERRγ inhibitor; and sorafenib as active ingredients.

[0035] In addition, the present invention provides a use for preventing, ameliorating or treating liver cancer of an ERRγ inhibitor; and a composition containing sorafenib as an active ingredient.

[0036] In one embodiment of the present invention, the composition can enhance the susceptibility of liver cancer to sorafenib or enhance the anti-cancer effect of sorafenib on liver cancer, but is not limited thereto.

[0037] In another embodiment of the present invention, the composition can be administered simultaneously, separately or sequentially with sorafenib, but is not limited thereto.

[0038] The present invention also provides a method for screening a substance for enhancing the treatment of sorafenib-resistant liver cancer, including the steps of treating a candidate substance with sorafenib-resistant liver cancer cells; and evaluating the activity or expression of ERRγ in the cells.

[0039] The present invention also provides a kit for diagnosing sorafenib-resistant liver cancer, including a preparation for measuring the level of mRNA of the ERRγ (Estrogen-related receptor γ) gene or the protein expressed therefrom.

[0040] In one embodiment of the present invention, the preparation for measuring the mRNA level of the gene may include a primer pair, a probe or an antisense nucleotide that specifically binds to the gene, but is not limited thereto.

[0041] In another embodiment of the present invention, the preparation for measuring the protein level may include an antibody or an aptamer specific for the protein, but is not limited thereto.

[0042] In yet another embodiment of the present invention, the kit may be an RT-PCR kit, a competitive RT-PCR kit, a real-time RT-PCR kit, a DNA chip kit, or a protein chip kit, but is not limited thereto.

[0043] The present invention also provides a method for providing information for diagnosing sorafenib-resistant liver cancer, comprising the following steps: (a) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient to be tested for sorafenib resistance; (b) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who does not have sorafenib-resistant liver cancer; and (c) When the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient.

[0044] Moreover, the present invention provides a method for providing information necessary for determining a treatment method for a liver cancer patient, comprising the following steps: (a) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient; (b) Measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who does not have sorafenib-resistant liver cancer; and (c) When the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient.

[0045] The present invention also provides a method for diagnosing and treating sorafenib-resistant liver cancer, comprising the following steps: (a) Measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient; (b) Measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who does not have sorafenib-resistant liver cancer; and (c) When the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient, and applying other liver cancer therapeutic agents other than sorafenib.

[0046] In one embodiment of the present invention, the biological sample may be, but is not limited to, liver tissue, hepatocytes, whole blood, plasma, serum, or blood.

Advantages of the Invention

[0047] According to the present invention, an ERRγ (Estrogen-related receptor γ) inhibitor has the effect of increasing the anti-cancer drug sensitivity to sorafenib, suppressing the proliferation of sorafenib-resistant liver cancer cells, and significantly reducing the size of liver cancer. Therefore, the present invention is expected to be usefully used as a pharmaceutical composition for treating sorafenib-resistant progressive liver cancer. In addition, through the method for providing information for diagnosing sorafenib-resistant liver cancer of the present invention, the therapeutic responsiveness of a liver cancer patient to sorafenib can be predicted, and a treatment strategy can be established customized for the patient based on the prediction result, so that liver cancer can be effectively treated.

Brief Description of the Drawings

[0048]

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Mode for Carrying Out the Invention

[0049] The present invention provides a formulation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein or the expression of the ERRγ gene for use in preventing or enhancing the treatment of sorafenib-resistant liver cancer.

[0050] In connection with this, the present invention provides a pharmaceutical composition for preventing or enhancing the treatment of sorafenib-resistant liver cancer, containing, as an active ingredient, a formulation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein or the expression of the ERRγ gene.

[0051] As another aspect of the present invention, the present invention provides a formulation capable of suppressing the activity of ERRγ protein or the expression of the ERRγ gene for use in suppressing sorafenib resistance during the prevention or treatment of liver cancer.

[0052] In connection with this, the present invention provides a pharmaceutical composition for suppressing sorafenib resistance in liver cancer, containing, as an active ingredient, a formulation capable of suppressing the activity of ERRγ protein or the expression of the ERRγ gene.

[0053] In yet another aspect of the present invention, the present invention provides a preparation capable of suppressing the activity of ERRγ protein or the expression of ERRγ gene for use in the prevention or treatment of liver cancer; and a composition containing sorafenib.

[0054] In connection therewith, the present invention provides a preparation capable of suppressing the activity of ERRγ protein or the expression of ERRγ gene; and a pharmaceutical composition for the prevention or treatment of liver cancer containing sorafenib as an active ingredient.

[0055] As used herein, the term "liver cancer" means a primary malignant tumor that occurs primarily in the liver. Pathologically (histologically), primary liver cancer includes various types such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, etc. Among these, hepatocellular carcinoma and cholangiocarcinoma account for the majority.

[0056] In the present invention, the liver cancer may be, but is not limited to, hepatocellular carcinoma (HCC).

[0057] As used herein, the term "treatment enhancement" means all acts in which the symptoms of sorafenib-resistant liver cancer are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention after acquisition of resistance to sorafenib in liver cancer.

[0058] As used herein, the term "treatment" means all acts in which the symptoms caused by liver cancer are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention before or after acquisition of resistance to sorafenib in liver cancer.

[0059] In the present invention, the pharmaceutical composition of the present invention can enhance the drug susceptibility to sorafenib or enhance the anti-cancer effect of sorafenib against liver cancer, but is not limited thereto.

[0060] In one embodiment of the present invention, Huh7-SR or SK-Hep-R cell lines were constructed as sorafenib-resistant liver cancer cell lines, and it was confirmed that the orphan nuclear receptor ERRγ (Estrogen-related receptor γ) was significantly increased in the liver cancer cell lines that acquired sorafenib resistance (see Example 1).

[0061] Also, in one embodiment of the present invention, as a result of treating sorafenib-resistant liver cancer cells with the compound (DN200434) represented by the chemical formula 1 which is an ERRγ inverse agonist, it was confirmed that ROS increased, and it was confirmed that the proliferation of resistant liver cancer cells that had no effect when treated with sorafenib alone decreased by the combined treatment of the compound represented by the chemical formula 1 and sorafenib. Thus, it was confirmed that the compound represented by the chemical formula 1 exhibits an effect of overcoming drug resistance by increasing the sensitivity to sorafenib through suppressing the activity of ERRγ (see Example 2).

[0062] Moreover, in one embodiment of the present invention, after administering sorafenib and the compound represented by the chemical formula 1 in combination to a sorafenib-resistant liver cancer animal model, as a result of measuring the size change of the formed tumor, it was confirmed that the size of liver cancer decreased significantly compared to the control group (sorafenib alone treatment group) (see Example 3).

[0063] In the present invention, the preparation for suppressing the activity of the ERRγ protein may be an inverse agonist or antagonist for ERRγ, or an antibody or aptamer that can specifically bind to ERRγ, but is not limited thereto.

[0064] As used herein, the term "Inverse agonist" or "antagonist" means a molecule that can directly or indirectly decrease the biological activity of a receptor, and includes a molecule that can decrease the action of the ligand when used together with the ligand of the receptor, but is not limited thereto.

[0065] As used herein, the term "antibody" means a proteinaceous molecule capable of specifically binding to an antigenic site of a protein or peptide molecule, and such an antibody can be obtained by cloning each gene into an expression vector by a conventional method to obtain the protein encoded by the marker gene, and can be produced from the obtained protein by a conventional method.

[0066] As used herein, the term "aptamer" means a nucleic acid molecule having binding activity to a predetermined target molecule. The aptamer may be RNA, DNA, modified nucleic acid, or a mixture thereof, and may be in a linear or cyclic form. Generally, the shorter the nucleotide sequence constituting the aptamer, the easier it is for chemical synthesis and mass production, it has advantages in terms of cost, is easy for chemical modification, has excellent in vivo stability, and is known to have low toxicity.

[0067] The inverse agonist and antagonist may be compounds.

[0068] In the present invention, the inverse agonist for ERRγ may be a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, but is not limited thereto.

[0069]

Chemical formula

[0070] As used herein, the term "pharmaceutically acceptable" means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic reaction, or other problems or complications, and has a reasonable benefit / risk ratio within the scope of sound medical judgment.

[0071] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts, and as salts, acid addition salts formed by pharmaceutically acceptable free acids are useful.

[0072] The acid addition salts can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.

[0073] Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0074] The acid addition salts according to the present invention can be prepared by a conventional method, for example, dissolving the compound of Chemical Formula 1 in an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Also, after evaporating the solvent and the excess acid from this mixture, it can be produced by drying or suction filtering the precipitated salt.

[0075] Also, pharmaceutically acceptable metal salts can be prepared using a base. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound of Chemical Formula 1 in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to produce sodium, potassium or calcium salts as the metal salts. The corresponding silver salts are obtained by reacting the alkali metal or alkaline earth metal salts with a suitable silver salt (for example, silver nitrate).

[0076] The scope of the compounds of the present invention can include not only pharmaceutically acceptable salts but also all isomers, hydrates and solvates that can be produced by conventional methods.

[0077] In the present invention, the preparation for suppressing the expression of the ERRγ gene can be selected from the group consisting of miRNA, siRNA, shRNA and antisense oligonucleotides that specifically bind to the mRNA of the gene, but is not limited thereto.

[0078] As used herein, the terms "miRNA, siRNA and shRNA" mean nucleic acid molecules that mainly bind to mRNA transcribed from a target gene to inhibit the translation of the mRNA in order to mediate RNA interference or gene silencing. Since the miRNA, siRNA and shRNA can suppress the expression of the target gene at the translation level, they can be used in efficient gene knockdown methods or gene therapy methods.

[0079] As used herein, the term "antisense oligonucleotide" means a DNA or RNA or a derivative thereof containing a nucleic acid sequence complementary to the sequence of a specific mRNA, but can bind to the complementary sequence in the mRNA and exhibit the effect of inhibiting the translation of the mRNA into protein.

[0080] On the other hand, the pharmaceutical composition according to the present invention may further contain a suitable carrier, excipient and / or diluent commonly used for producing the pharmaceutical composition in addition to the active ingredient. Also, it can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions by ordinary methods.

[0081] Examples of the carrier, excipient and diluent that may be contained in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulating the composition, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants commonly used.

[0082] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined by factors including the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the administration time, the administration route and excretion ratio, the treatment period, elements including drugs used simultaneously, and other elements well known in the medical field.

[0083] In the present invention, the pharmaceutical composition of the present invention can be administered simultaneously, separately or sequentially with sorafenib, and can be administered singly or multiply.

[0084] It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects considering all of the above-described elements, which can be determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention can vary depending on the patient's age, sex, condition, weight, absorption degree of the active ingredient in the body, inactivation rate and excretion rate, type of disease, and drugs used in combination.

[0085] The pharmaceutical composition of the present invention can be administered to an individual by various routes. For example, it can be administered by oral administration, intranasal administration, intratracheal administration, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection or intraperitoneal injection. The daily dose can be administered once a day or divided into several times a day.

[0086] In still another aspect of the present invention, the present invention provides a method for preventing or enhancing the treatment of sorafenib-resistant liver cancer, which includes the step of administering an ERRγ inhibitor to an individual.

[0087] Specifically, the present invention provides a method for preventing or enhancing the treatment of sorafenib-resistant liver cancer, which includes the step of administering an ERRγ inhibitor to a patient with sorafenib-resistant liver cancer.

[0088] In still another aspect of the present invention, the present invention provides a method for suppressing sorafenib resistance in liver cancer, which includes the step of administering an ERRγ inhibitor to an individual.

[0089] Specifically, the present invention provides a method for suppressing sorafenib resistance in liver cancer, which includes the step of administering an ERRγ inhibitor to a patient with sorafenib-resistant liver cancer.

[0090] In yet another aspect of the present invention, the present invention provides a method for preventing or treating liver cancer, which includes administering to an individual a composition containing an ERRγ inhibitor and sorafenib as active ingredients.

[0091] Specifically, the present invention provides a method for preventing or treating liver cancer, which includes administering an ERRγ inhibitor and sorafenib to a liver cancer patient.

[0092] In the method of the present invention, the liver cancer may be, but is not limited to, sorafenib-resistant liver cancer.

[0093] As used herein, the term "individual" means a subject in need of prevention, treatment, treatment enhancement or resistance suppression of a disease. For example, the individual may be a mammal including a human, or a non-human primate, mouse, dog, cat, horse, sheep and cow.

[0094] In yet another aspect of the present invention, the present invention provides a method for screening a substance for enhancing the treatment of sorafenib-resistant liver cancer, which includes: (a) treating a candidate substance with sorafenib-resistant liver cancer cells; and (b) evaluating the activity or expression of ERRγ in the cells. Through the method as described above, a substance capable of suppressing the activity or expression of ERRγ in sorafenib-resistant liver cancer cells can be selected, and this can be used as an enhancer or adjuvant for the treatment of sorafenib-resistant liver cancer.

[0095] In yet another aspect of the present invention, the present invention provides a kit for diagnosing sorafenib-resistant liver cancer.

[0096] Specifically, the kit for diagnosing sorafenib-resistant liver cancer includes a preparation for measuring the level of mRNA of the ERRγ gene or the protein expressed therefrom.

[0097] In the present invention, the term "diagnosis" means to confirm the existence or characteristics of a pathological condition. In the present invention, the diagnosis is to measure the level of mRNA of the ERRγ gene or the protein expressed therefrom to confirm the presence or absence of the occurrence of sorafenib-resistant liver cancer.

[0098] In the present invention, the term "agent for measuring the mRNA of ERRγ or the protein expression level thereof" means a molecule that can be used to confirm the expression level of the ERRγ gene of the present invention or the protein encoded by these genes, and preferably, it can be a primer pair, a probe or an antisense nucleotide that specifically binds to the ERRγ gene, or an antibody or an aptamer specific to the protein encoded by the ERRγ gene.

[0099] In the present invention, the term "primer" refers to a nucleic acid sequence having a short free 3' hydroxyl group, which can form base pairs with a complementary template and functions as a starting point for the copy of the template. In the present invention, PCR amplification can be carried out using the sense and antisense primers of the marker polynucleotide of the present invention to screen patients with sorafenib-resistant liver cancer through the degree of generation of the desired product. The PCR conditions and the lengths of the sense and antisense primers can be modified based on those known in the art.

[0100] In the present invention, the term "probe" means a nucleic acid fragment such as RNA or DNA corresponding to a short oligonucleotide of several bases to a long oligonucleotide of several hundred bases that can specifically bind to mRNA, which is labeled and can confirm the presence or absence of a specific mRNA. The probe can be prepared in the form of an oligonucleotide probe, a single-stranded DNA probe, a double-stranded DNA probe, an RNA probe, etc. In the present invention, hybridization is carried out using a probe complementary to the ERRγ polynucleotide of the present invention, and patients with sorafenib-resistant liver cancer can be screened through the degree of hybridization. The selection of an appropriate probe and hybridization conditions can be modified based on those known in the art.

[0101] The primer or probe of the present invention can be chemically synthesized using the phosphoramidite solid support method or other widely known methods. Such nucleic acid sequences can also be modified using many means known in the art. Non-limiting examples of such modifications include methylation, capping, substitution of one or more natural nucleotides with analogs, and modifications between nucleotides, such as modifications to uncharged linkers (e.g., methylphosphonate, phosphotriester, phosphoramidate, carbamate, etc.) or charged linkers (e.g., phosphorothioate, phosphorodithioate, etc.).

[0102] Considering mutations with biologically equivalent activities, the nucleotide sequence of the agent for measuring the expression level of the ERRγ gene used in the present invention is also interpreted to include sequences that exhibit substantial identity with sequences that specifically bind to the ERRγ gene. The term "substantial identity" means that when a specific sequence and any other sequence are aligned to maximize correspondence and the aligned sequences are analyzed using algorithms commonly used in the art, it refers to sequences showing at least 60% identity, more specifically 70% identity, even more specifically 80% identity, and most specifically 90% identity.

[0103] In the kit of the present invention, since the terms "antibody" and "aptamer" are the same as those described above in the pharmaceutical composition, their descriptions are omitted.

[0104] The kit of the present invention can be used to diagnose sorafenib-resistant liver cancer or predict the therapeutic responsiveness to sorafenib by confirming the mRNA expression level of the ERRγ gene or the expression level of the protein encoded by these genes.

[0105] From the perspective that the kit of the present invention can be used to predict the therapeutic responsiveness to sorafenib, it can be used for the purpose of predicting the prognosis of liver cancer patients.

[0106] In the present invention, the term "prognosis prediction" means the outlook for the medical course, and for the purpose of the present invention, it means predicting the resistance of liver cancer patients to sorafenib.

[0107] According to one embodiment of the present invention, the kit may be, but is not limited to, an RT-PCR kit, a competitive RT-PCR kit, a real-time RT-PCR kit, a DNA chip kit, or a protein chip kit.

[0108] According to one embodiment of the present invention, a kit for measuring the mRNA expression level of the ERRγ gene can be a kit containing essential elements necessary for performing RT-PCR. The RT-PCR kit may include, in addition to each specific primer pair for the marker gene, test tubes or other suitable containers, reaction buffers, deoxynucleotides (dNTPs), Taq-polymerase and reverse transcriptase, DNase, RNase inhibitors, DEPC-water, sterile water, and the like.

[0109] The kit of the present invention can include a kit for extracting nucleic acids (e.g., total RNA) from body fluids, cells, or tissues, a fluorescent substance for labeling, an enzyme for nucleic acid amplification, a medium, an instruction manual, and the like.

[0110] According to another embodiment of the present invention, the kit of the present invention can be a kit for detecting ERRγ containing essential elements necessary for performing a DNA chip. The DNA chip kit includes a substrate to which cDNA corresponding to a gene or a fragment thereof is attached as a probe, and the substrate may include cDNA corresponding to a quantitative control group gene or a fragment thereof.

[0111] According to still another embodiment of the present invention, a kit for measuring the expression level of the protein encoded by ERRγ in the present invention may include a substrate for immunological detection of an antibody, a suitable buffer solution, a secondary antibody labeled with a chromogenic enzyme or a fluorescent substance, a chromogenic substrate, and the like. The substrate described above can be a nitrocellulose membrane, a 96-well plate synthesized from polyvinyl resin, a 96-well plate synthesized from polystyrene resin, a slide glass made of glass, etc. The chromogenic enzyme can be peroxidase, alkaline phosphatase, and the fluorescent substance can be FITC, RITC, etc. The chromogenic substrate solution can be ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethylbenzidine), etc.

[0112] The kit of the present invention can further include a composition, solution or device having one or more other components suitable for the analysis method.

[0113] In still another aspect, the present invention provides a method for providing information for the diagnosis of sorafenib-resistant liver cancer.

[0114] Specifically, the method for providing information for the diagnosis of sorafenib-resistant liver cancer includes: (a) measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient who is to be confirmed for resistance to sorafenib; (b) measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who does not have sorafenib-resistant liver cancer; and (c) when the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient.

[0115] In the present invention, the term "biological sample" includes tissues (liver tissues), cells (hepatocytes), whole blood, plasma, serum, blood, saliva, synovial fluid, urine, sputum, lymph fluid, cerebrospinal fluid, tissue autopsy samples (brain, skin, lymph nodes, spinal cord, etc.), cell culture supernatants, or lysed eukaryotic cells, etc., in which the expression and / or activity levels of ERRγ, a sorafenib-resistant liver cancer marker, are different, and includes samples derived not only from the primary tumor locus of cancer but also from metastatic tumor loci. The activity or expression level of ERRγ can be confirmed with or without manipulating these biological samples.

[0116] In the method for providing information for diagnosing sorafenib-resistant liver cancer of the present invention, the biological sample in the step (a) can be obtained by using a specific method known to those skilled in the art. For example, the biological sample can be obtained from a vertebrate, particularly a mammal, and preferably can be obtained from a liver cancer patient who is to be confirmed whether showing resistance to sorafenib. Here, the liver cancer patient is a human. Tissue biopsy is often used to obtain a representative section of the tumor tissue. Optionally, the tumor cells can be obtained indirectly in the form of a tissue or fluid known or suspected to contain the tumor cells of interest.

[0117] In the present invention, the term "measurement of mRNA expression level" is a process of confirming the presence and expression level of mRNA of the ERRγ gene in a biological sample, and can be known by measuring the amount of mRNA. Analytical methods for this purpose include, but are not limited to, RT-PCR, competitive RT-PCR, Real-time RT-PCR, RNase protection method, northern blotting, or DNA chip technology.

[0118] In the present invention, the term "measurement of protein expression level" is a process of confirming the presence or absence and the degree of expression of a protein expressed by the ERRγ gene in a biological sample, and the amount of the protein can be confirmed using an antibody that specifically binds to the protein expressed by the gene. Analytical methods for this purpose include, but are not limited to, western blotting, ELISA (enzyme linked immunosorbent assay), RIA (radioimmunoassay), radial immunodiffusion, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, immunohistochemical staining, immunoprecipitation assay, complement fixation assay, immunofluorescence, immunochromatography, FACS analysis (fluorescence-activated cell sorter analysis), or protein chip technology.

[0119] In the method for providing information for diagnosing sorafenib-resistant liver cancer of the present invention, patients with general liver cancer who do not have sorafenib-resistant liver cancer may be patients with hepatocellular carcinoma (HCC) or hepatic adenocarcinoma that do not show sorafenib-resistant liver cancer, but are not limited thereto.

[0120] In the method for providing information for diagnosing sorafenib-resistant liver cancer of the present invention, the expression level of the ERRγ gene can be measured at the mRNA level or the protein level, and the separation of mRNA or protein in a biological sample can be performed using known procedures. The analysis method for measuring the mRNA level and the analysis method for measuring the protein level are the same as those described above.

[0121] Through the method for providing information for diagnosing sorafenib-resistant liver cancer of the present invention, the treatment responsiveness of a liver cancer patient to sorafenib can be predicted, and a treatment strategy can be established by customizing it for the patient based on the prediction result, and liver cancer can be effectively treated.

[0122] Furthermore, in another aspect, the present invention provides a method for providing information necessary for determining a treatment method for a liver cancer patient, including the step of measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from the liver cancer patient.

[0123] Specifically, the method for providing information necessary for determining a treatment method for a liver cancer patient includes: (a) measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from the liver cancer patient; (b) measuring the expression level of mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who is not sorafenib-resistant liver cancer; and (c) when the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient.

[0124] When the resistance of a liver cancer patient to sorafenib is confirmed by the method for providing information necessary for determining a treatment method for the liver cancer patient, other known liver cancer therapeutic agents excluding sorafenib can be applied to induce a liver cancer treatment effect.

[0125] Accordingly, from a further perspective, the present invention provides a method for diagnosing and treating sorafenib-resistant liver cancer.

[0126] Specifically, the method for diagnosing and treating sorafenib-resistant liver cancer according to the present invention comprises: (a) measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a liver cancer patient; (b) measuring the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom in a biological sample isolated from a general liver cancer patient who does not have sorafenib-resistant liver cancer; and (c) when the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (a) is higher than the expression level of the mRNA of the ERRγ gene or the protein expressed therefrom measured in step (b), determining the liver cancer patient in step (a) as a sorafenib-resistant liver cancer patient, and applying a liver cancer therapeutic agent other than sorafenib.

[0127] The method for providing information necessary for determining the treatment method of a liver cancer patient according to the present invention and / or the specific content of the method for diagnosing and treating sorafenib-resistant liver cancer are the same as the method for providing information for diagnosing sorafenib-resistant liver cancer described above, and thus the description thereof is omitted.

[0128] The terms and words used in this specification and the claims should not be construed as being limited to their ordinary or dictionary meanings. The inventor stands on the principle that he can appropriately define the concept of the terms in order to explain his invention in the best way, and thus they should be construed in a meaning and concept that conforms to the technical idea of the present invention.

[0129] Hereinafter, preferred examples are presented to assist in understanding the present invention. However, the following examples are provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.

[0130] [Experimental Example] General experimental methods The inventors conducted experiments by utilizing sorafenib-resistant liver cancer cell lines (Huh7-SR cell line, SK-Hep-R cell line) and animal models (xenograft) derived from liver cancer cell lines. To confirm the effects of the synthetic compound DN200434, an inverse agonist of ERRγ, on the proliferation of liver cancer cells and ROS, cell count and DCF-DA (2’,7’-dichlorofluorescin diacetate) were used to measure ROS. Finally, sorafenib-resistant liver cancer cell lines were injected into white mice to induce the formation of sorafenib-resistant liver cancer, and then the change in the size of liver cancer was confirmed in the group injected with the ERRγ inverse agonist DN200434 and sorafenib and the group injected with the control drug.

[0131] [Example 1] Construction of sorafenib-resistant liver cancer cell lines and confirmation of increased ERRγ expression Hepatocellular carcinoma cell lines [Huh7 cell (Korean Cell Line Bank KCLB No. 60104), SK-Hep cell (ATCC® HTB-52TM)] were continuously exposed to sorafenib (gradually increasing to 10 μM), and sorafenib-resistant hepatocellular carcinoma cell lines (Huh7-SR cell line, SK-Hep-R cell line) were constructed. First, to evaluate cancer cell death by FACS, cancer cell lines were cultured with FITC-conjugated Annexin and propidium iodide (PI) for 15 minutes, and then the binding of Annexin and PI was measured by flow cytometry. Data were acquired using a BD accuri C6 flow cytometry device (BD biosciences) and analyzed using the Accuri C6 analysis program (BD Biosciences) / FlowJo software (FlowJo, LLC.). Cancer cell line death was evaluated using a Cleaved caspase-3 antibody (Cell Signaling Technology). As shown in FIGS. 1a to 1c, it was confirmed that in both the Huh7-SR cell line and the SK-Hep-R cell line, which are sorafenib-resistant hepatocellular carcinoma cell lines, cell death did not increase due to sorafenib.

[0132] In addition, to confirm the expression pattern of the orphan nuclear receptor ERRγ in the Huh7-SR cell line and the SK-Hep-R cell line, Western blot was performed. As shown in FIGS. 2a and 2b, it was confirmed that the expression of ERRγ was significantly increased in both of the two sorafenib-resistant hepatocellular carcinoma cell lines.

[0133] [Example 2] Elucidation of the effect of the orphan nuclear receptor ERRγ on sorafenib-resistant hepatocellular carcinoma To correct the effect of the compound DN200434 represented by Chemical Formula 1, which is an ERRγ inverse agonist, on ROS production in sorafenib-resistant liver cancer cells, it was measured by FACS using the ROS probe H2-DCF-DA (2’,7’-dichlorohydrofluorescein diacetate; Invitrogen, USA). After treating sorafenib (10 μM) and the DN200434 compound (12 μM) on drug-resistant cells for 24 hours, 10 μM of H2-DCF-DA was added to the cells and cultured for 30 minutes. After washing with PBS, data was collected using a BD AccuriTM C6 flow cytometry device (BD Bioscience, USA) and analyzed using the AccuriTM C6 analysis program (BD Bioscience, USA). The evaluation of the cell count was performed by treating the sorafenib-resistant liver cancer cell line with sorafenib (10 μM) and the DN200434 compound (12 μM) in combination, staining with Trypan blue, and then measuring the cell count using a hemocytometer.

[0134] As a result, as shown in FIGS. 3a and 3b, it was confirmed that ROS increased in both the Huh7-SR cell line and the SK-Hep-R cell line, which are sorafenib-resistant liver cancer cell lines, by the DN200434 compound. As shown in FIGS. 4a and 4b, it was confirmed that the cell growth of drug-resistant liver cancer cells that had no effect when treated with sorafenib alone was significantly decreased by the co-administration of DN200434 represented by the above Chemical Formula 1. Through the above results, it was confirmed that DN200434 can overcome drug resistance by suppressing ERRγ activity and increasing sensitivity to sorafenib.

[0135] [Example 3] Confirmation of the anti-cancer effect in a sorafenib-resistant liver cancer animal model The sorafenib-resistant liver cancer cell line Huh7-R was injected into mice to construct a sorafenib-resistant liver cancer animal model (xenograft). Subsequently, after co-administering the ERRγ inverse agonist, DN200434 (chemical formula 1), with sorafenib, the change in the size of the formed tumor was measured. Here, the group treated with only sorafenib in the sorafenib-resistant liver cancer animal model was used as the comparison control group.

[0136] As a result, as shown in FIGS. 5a to 5c, in the group co-administering the DN200434 compound represented by the chemical formula 1, which is an ERRγ inverse agonist, with sorafenib in the animal model derived from the sorafenib-resistant liver cancer cell line Huh7-R, it was confirmed that the size, weight, and volume of the liver cancer tumors were significantly reduced compared to the control group. Here, as can be confirmed from FIG. 5d, there was no difference in the body weight change between the experimental group and the control group.

[0137] Using the same method as above, an animal model derived from the sorafenib-resistant liver cancer cell line SK-Hep-R was established, and the combined administration effect of the DN200434 compound represented by the chemical formula 1, which is an ERRγ inverse agonist, and sorafenib was confirmed.

[0138] Similarly, as shown in FIGS. 6a to 6c, in the animal model derived from the sorafenib-resistant liver cancer cell line SK-Hep-R, it was also confirmed that in the group co-administering the DN200434 compound and sorafenib, the size, weight, and volume of the liver cancer tumors were significantly reduced compared to the control group. As can be confirmed from FIG. 6d, there was no difference in the body weight change between the experimental group and the control group.

[0139] Taking the results of Examples 1 to 3 together, it was confirmed that the expression of ERRγ increases significantly in sorafenib-resistant liver cancer, and it was confirmed in a cell experiment that the ERRγ inverse agonist represented by Chemical Formula 1, DN200434, increases intracellular ROS, thereby inhibiting the proliferation of sorafenib-resistant liver cancer cells and increasing their sensitivity to sorafenib. In addition, in an animal experiment using a sorafenib-resistant liver cancer cell line, it was confirmed that the cancer proliferation was significantly reduced compared to the control group. The above results prove that ERRγ plays an important role in the drug resistance of liver cancer, and that when the activity of ERRγ is inhibited using the ERRγ inverse agonist, DN200434, it is effective in treating drug-resistant advanced liver cancer.

[0140] The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified in other specific forms without changing the technical concept or essential features of the present invention. Therefore, the above-described embodiments should be understood to be illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing or enhancing the treatment of sorafenib-resistant liver cancer, comprising as an active ingredient a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, 【Chemical 1】 and the composition is administered simultaneously, separately, or sequentially with sorafenib pharmaceutical composition.

2. The pharmaceutical composition according to Claim 1, wherein the composition enhances the drug susceptibility of liver cancer to sorafenib or enhances the anti-cancer effect of sorafenib against liver cancer.

3. A pharmaceutical composition for suppressing sorafenib resistance in liver cancer, comprising as an active ingredient a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, 【Chemical 2】 and the composition is administered simultaneously, separately, or sequentially with sorafenib pharmaceutical composition.

4. A pharmaceutical composition for preventing or treating sorafenib-resistant liver cancer, comprising a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein; and sorafenib as active ingredients, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. [Chemical 3]

5. Use of a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein for manufacturing a pharmaceutical for preventing or enhancing the treatment of sorafenib-resistant liver cancer, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, 【Chemical Formula 4】 and the preparation is administered simultaneously, separately, or sequentially with sorafenib use.

6. The use according to claim 5, wherein the preparation enhances the drug susceptibility of sorafenib to liver cancer or enhances the anti-cancer effect of sorafenib against liver cancer.

7. Use of a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein for manufacturing a pharmaceutical product for suppressing sorafenib resistance in liver cancer, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof, 【Chemical Formula 5】 and the preparation is administered simultaneously, separately or sequentially with sorafenib Use.

8. Use of a preparation capable of suppressing the activity of ERRγ (Estrogen-related receptor γ) protein for manufacturing a pharmaceutical product for preventing or treating sorafenib-resistant liver cancer; and a composition comprising sorafenib, wherein the preparation capable of suppressing the activity of the ERRγ protein is a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. 【Chemical Formula 6】

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