PHARMACOPROTEOMICS PLATFORM IDENTIFYING KINOME FEATURES REGULATING DRUG RESPONSE IN CANCER
The disclosure provides methods and compositions for increasing sensitivity, or decreasing resistance, of cancer cells to chemotherapeutic agents such as kinase inhibitor agents. In some embodiments, the cancer cells are hepatocellular carcinoma (HCC) cells. The methods and compositions can be integrated into methods of treatment of a subject with cancer, which can further comprise administering a chemotherapeutic agent such as kinase inhibitor agents. In another aspect, the disclosure provides a method for profiling the kinome of a cell or group of similar cells that incorporates kinase capture reagents and mass spectrometry analysis.
1 . A method of reducing resistance in a cancer cell to a chemotherapeutic agent, comprising contacting the cell with an agent that inhibits the expression or function of an epithelial-mesenchymal transition (EMT)-associated kinase.
2 . The method of claim 1 , wherein the chemotherapeutic agent is kinase inhibitor.
3 . The method of claim 2 , wherein the kinase inhibitor is selected from Table 1.
4 . The method of claim 2 , wherein the kinase inhibitor is an inhibitor of a kinase selected from EGFR, SRC, c-MET, RAF, IGH1R, MEK1/2, PI3K, CHECK1/2, PLK1, CDK1/2, FGFR, mTOR, and AURK.
5 . The method of claim 2 , wherein the kinase inhibitor is selected from sorafenib, regorafenib, lenvatinib, cabozantinib, dinaciclib, tezolizumab, ramucirumab, and becacizumab.
6 . The method of claim 1 , wherein the cancer cell is a hepatocellular carcinoma cell.
7 . The method of claim 1 , wherein contacting the cell with the agent prevents or reverses transition of the cancer cell from an epithelial phenotype to a mesenchymal phenotype.
8 . The method of claim 1 , wherein the EMT-associated kinase is selected from the kinases listed in Table 2.
9 . The method of claim 1 , wherein the EMT-associated kinase is selected from AXL, MET, EPHB2, FYN, AKT3, CAMK1D, NUAK1, NUAK2, EPHA4, CAMK1D, FYN, NEK3, CDK3, PLK1, CHEK1, EGFR, HIPK2, TNK2, LYN, PTK2, MAP3K12, MAPK9, MAPK8, FER, AAK1, CDK10, STK17B, and STK32B.
10 . The method of claim 1 , further comprising contacting the cell with the chemotherapeutic agent.
11 . The method of claim 1 , wherein the cell is contacted in vivo in a subject with cancer, and the method comprises administering a therapeutically effective amount of the agent that inhibits the expression or function of the EMT-associated kinase.
12 . A method of enhancing sensitivity of a cancer cell to a kinase inhibitor therapy in a subject in need thereof, comprising administering to the subject an effective amount of an agent that inhibits the expression or function of an epithelial-mesenchymal transition (EMT)-associated kinase.
13 . The method of claim 12 , wherein the kinase inhibitor is selected from Table 1.
14 . The method of claim 12 , wherein the kinase inhibitor is an inhibitor of a kinase selected from EGFR, SRC, c-MET, RAF, IGH1R, MEK1/2, PI3K, CHECK1/2, PLK1, CDK1/2, FGFR, mTOR, and AURK.
15 . The method of claim 12 , wherein the kinase inhibitor is selected from sorafenib, regorafenib, lenvatinib, cabozantinib, dinaciclib, tezolizumab, ramucirumab, and becacizumab.
16 . The method of claim 12 , wherein the cancer cell is a hepatocellular carcinoma cell.
17 . The method of claim 12 , wherein administering the agent prevents or reverses transition of the cancer cell from an epithelial phenotype to a mesenchymal transition phenotype.
18 . The method of claim 12 , wherein the EMT-associated kinase is selected from the kinases listed in Table 2.
19 . The method of claim 12 , wherein the EMT-associated kinase is selected from AXL, MET, EPHB2, FYN, AKT3, CAMK1D, NUAK1, NUAK2, EPHA4, CAMK1D, FYN, NEK3, CDK3, PLK1, CHEK1, EGFR, HIPK2, TNK2, LYN, PTK2, MAP3K12, MAPK9, MAPK8, FER, AAK1, CDK10, STK17B, and STK32B.
20 . The method of claim 12 , wherein the method is a method for treating the cancer and further comprises administering a therapeutically effective amount of the chemotherapeutic agent to the subject.