Biological markers predictive of anti-cancer response to epidermal growth factor receptor kinase inhibitors

Abstract

The present invention provides diagnostic and prognostic methods for predicting the effectiveness of treatment of a cancer patient with an EGFR kinase inhibitor. Methods are provided for predicting the sensitivity of tumor cell growth to inhibition by an EGFR kinase inhibitor, comprising assessing whether the tumor cell has undergone an epithelial to mesenchymal transition (EMT), by determining the expression level of epithelial and/or mesenchymal biomarkers, wherein tumor cells that have undergone an EMT are substantially less sensitive to inhibition by EGFR kinase inhibitors. Improved methods for treating cancer patients with EGFR kinase inhibitors that incorporate the above methodology are also provided. Additionally, methods are provided for the identification of new biomarkers that are predictive of responsiveness of tumors to EGFR kinase inhibitors. Furthermore, methods for the identification of agents that restore the sensitivity of tumor cells that have undergone EMT to inhibition by EGFR kinase inhibitors are also provided.

1 .- 21 . (canceled) 
     
     
         22 . A method of treating tumors or tumor metastases comprising administering to a patient in need thereof a therapeutically effective amount of one or more EGFR kinase inhibitors, wherein said patient's tumor cells have not undergone an epithelial-mesenchymal transition. 
     
     
         23 . The method of  claim 22 , wherein said tumor cells express one or more of 1) a high level of one or more epithelial biomarkers; 2) a low or undetectable level of one or more mesenchymal biomarkers; and 3) a high ratio of one or more epithelial biomarkers to one or more mesenchymal biomarkers, sufficient to indicate said tumor cells have not undergone an epithelial-mesenchymal transition. 
     
     
         24 . The method of  claim 23 , wherein said epithelial biomarker is Brk, γ-catenin, α1-catenin, α2-catenin, α3-catenin, keratin 8, keratin 18, connexin 31, plakophilin 3, stratafin 1, laminin alpha-5, or ST14. 
     
     
         25 . The method of  claim 23 , wherein said mesenchymal biomarker is vimentin, fibronectin, fibrillin-2, collagen alpha-2(IV), collagen alpha-2(V), LOXL1, nidogen, C11orf9, tenascin, N-cadherin, and embryonal EDB +  fibronectin, tubulin alpha-3, or epimorphin. 
     
     
         26 . The method of  claim 22 , wherein said patient s human. 
     
     
         27 . The method of  claim 22 , wherein said tumor is lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer. 
     
     
         28 . The method of  claim 22 , wherein said EGFR kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 22 , wherein said patient is administered as least one other active agent. 
     
     
         30 . A method of treating tumors or tumor metastases comprising administering to a patient in need thereof a therapeutically effective amount of one or more EGFR kinase inhibitors, wherein said patient's tumor cells have been determined not to have undergone an epithelial-mesenchymal transition. 
     
     
         31 . The method of  claim 30 , wherein said determination is made by assessing if said tumor cells express one or more of 1) a high level of one or more epithelial biomarkers; 2) a low or undetectable level of one or more mesenchymal biomarkers; and 3) a high ratio of one or more epithelial biomarkers to one or more mesenchymal biomarkers. 
     
     
         32 . The method of  claim 31 , wherein said epithelial biomarker is Brk, γ-catenin, α1-catenin, α2-catenin, α3-catenin, keratin 8, keratin 18, connexin 31, plakophilin 3, stratafin 1, laminin alpha-5, or ST14. 
     
     
         33 . The method of  claim 31 , wherein said mesenchymal biomarker is vimentin, fibronectin, fibrillin-1, fibrillin-2, collagen alpha-2(IV), collagen alpha-2(V), LOXL1, nidogen, C11orf9, tenascin, N-cadherin, and embryonal EDB +  fibronectin, tubulin alpha-3, or epimorphin. 
     
     
         34 . The method of  claim 30 , wherein said patient is human. 
     
     
         35 . The method of  claim 30 , wherein said tumor is lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer. 
     
     
         36 . The method of  claim 30 , wherein said EGFR kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 30 , wherein said patient is administered as least one other active agent. 
     
     
         38 . A method of treating tumors or tumor metastases comprising administering to a human patient in need thereof a therapeutically effective amount of one or more EGFR kinase inhibitors, wherein said human patient's tumor cells have been determined not to have undergone an epithelial-mesenchymal transition by assessing if said tumor cells express one or more of 1) a high level of one or more epithelial biomarkers; 2) a low or undetectable level of one or more mesenchymal biomarkers; and 3) a high ratio of one or more epithelial biomarkers to one or more mesenchymal biomarkers, wherein said epithelial biomarker is Brk, γ-catenin, α1-catenin, α2-catenin, α3-catenin, keratin 8, keratin 18, connexin 31, plakophilin 3, stratafin 1, laminin alpha-5, or ST14, wherein said mesenchymal biomarker is vimentin, fibronectin, fibrillin-1, fibrillin-2, collagen alpha-2(IV), collagen alpha-2(V), LOXL1, nidogen, C11orf9, tenascin, N-cadherin, and embryonal EDB +  fibronectin, tubulin alpha-3, or epimorphin, and wherein said tumor is lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer. 
     
     
         39 . The method of  claim 38 , wherein said EGFR kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 38 , wherein said patient is administered as least one other active agent.