C-cbl mutations and uses thereof

Abstract

The present invention relates generally to the fields of molecular biology and growth factor regulation. The invention concerns methods and compositions useful for diagnosing and treating human lung cancer associated with mutated c-CBL.

1 . A method of identifying a subject that is susceptible to treatment with a c-Met inhibitor comprising determining whether a sample from the subject comprises a mutation in a nucleic acid sequence encoding human c-CBL, wherein the mutation results in an amino acid change at position S80N, H94Y, Q249E, V391I, 72515 — 72517delATG, W802*, R830K, A848T, L620F, P170L, S171S, L281F, L254S, or P782L. 
     
     
         2 . The method of  claim 1 , wherein the presence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is susceptible to treatment with a c-Met inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the absence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is not susceptible to treatment with a c-Met inhibitor. 
     
     
         4 . The method of  claim 1 , wherein the subject has been diagnosed with cancer. 
     
     
         5 . The method of  claim 1 , wherein the subject has cancer. 
     
     
         6 . The method of  claim 1 , wherein the sample is a cancer sample. 
     
     
         7 . A method of identifying a subject that is susceptible to treatment with a c-Met inhibitor comprising determining whether a sample from the subject comprises a mutation in a nucleic acid sequence encoding human c-CBL, wherein the mutation is located in the TKB domain, RING finger domain, proline-rich region, C-terminal region, or other domain linkage regions of c-CBL. 
     
     
         8 . The method of  claim 7 , wherein the presence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is susceptible to treatment with a c-Met inhibitor. 
     
     
         9 . The method of  claim 7 , wherein the absence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is not susceptible to treatment with a c-Met inhibitor. 
     
     
         10 . The method of  claim 7 , wherein the mutation results in an amino acid change at position S80N, H94Y, Q249E, V391I, 72515 — 72517delATG, W802*, R830K, A848T, L620F, P170L, S171S, L281F, L254S, or P782L. 
     
     
         11 . A method of identifying a cancer that is susceptible to treatment with a c-Met inhibitor, comprising determining whether a sample from the cancer comprises a mutation in a nucleic acid sequence encoding human c-CBL. 
     
     
         12 . The method of  claim 11 , wherein the presence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is susceptible to treatment with a c-Met inhibitor. 
     
     
         13 . The method of  claim 11 , wherein the absence of a mutation in a nucleic acid sequence encoding human c-CBL identifies a subject that is not susceptible to treatment with a c-Met inhibitor. 
     
     
         14 . The method of  claim 11 , wherein the mutation results in an amino acid change at position S80N, H94Y, Q249E, V391I, 72515 — 72517delATG, W802*, R830K, A848T, L620F, P170L, S171S, L281F, L254S, or P782L. 
     
     
         15 . The method of  claim 11 , wherein the mutation is located in the TKB domain, RING finger domain, proline-rich region, C-terminal region, or other domain linkage regions of c-CBL. 
     
     
         16 . A method of determining responsiveness of a cancer in a subject to treatment with a c-Met inhibitor, said method comprising determining whether a cancer sample from a subject comprises a mutation in a nucleic acid sequence encoding human c-CBL, wherein the mutation results in an amino acid change at position S80N, H94Y, Q249E, V391I, 72515 — 72517delATG, W802*, R830K, A848T, L620F, P170L, S171S, L281F, L254S, or P782L, wherein presence of the mutated nucleic acid sequence is indicative that the cancer is responsive to treatment with the c-Met inhibitor. 
     
     
         17 . A method of determining responsiveness of a cancer in a subject to treatment with a c-Met inhibitor, said method comprising determining whether a cancer sample from a subject comprises a mutation in a nucleic acid sequence encoding human c-CBL, wherein the mutation is located in the TKB domain, RING finger domain, proline-rich region, C-terminal region, or other domain linkage regions of c-CBL, wherein the presence of the mutated nucleic acid sequence is indicative that the cancer is responsive to treatment with the c-Met inhibitor. 
     
     
         18 . A method of detecting cancer in a sample comprising determining whether the sample comprises a mutation in a nucleic acid sequence encoding human c-CBL, wherein the mutation results in an amino acid change at position S80N, H94Y, Q249E, V391I, 72515 — 72517delATG, W802*, R830K, A848T, L620F, P170L, S171S, L281F, L254S, or P782L 
     
     
         19 . A method of identifying a subject that is susceptible to treatment with a c-Met inhibitor comprising determining the level of c-CBL expression in a sample from the subject. 
     
     
         20 . The method of  claim 19 , wherein low levels of c-CBL expression identify a subject that is susceptible to treatment with a c-Met inhibitor. 
     
     
         21 . The method of  claim 19 , wherein high levels of c-CBL expression identify a subject that is not susceptible to treatment with a c-Met inhibitor. 
     
     
         22 . A method of determining responsiveness of a cancer in a subject to treatment with a c-Met inhibitor, said method comprising determining the expression level of c-CBL in a cancer sample from the subject, wherein equal or higher levels of c-CBL expression in the cancer sample relative to a normal sample are indicative that the cancer is not susceptible to treatment with the c-Met inhibitor. 
     
     
         23 . A method of determining responsiveness of a cancer in a subject to treatment with a c-Met inhibitor, said method comprising determining the expression level of c-CBL in a cancer sample from the subject, wherein lower levels of c-CBL expression in the cancer sample relative to a normal sample are indicative that the cancer is susceptible to treatment with the c-Met inhibitor. 
     
     
         24 . The method of  claim 19 , wherein the expression level of c-CBL is determined by determining the amount of c-CBL RNA in the sample. 
     
     
         25 . The method of claims  claim 19 , wherein the expression level of c-CBL is determined by determining the amount of c-CBL protein in the sample. 
     
     
         26 . The method of claims  claim 19 , wherein the expression level of c-CBL is determined by determining the presence of loss of heterozygocity (LOH) at the c-CBL gene locus, wherein LOH at the c-CBL locus is indicative of lower c-CBL expression. 
     
     
         27 . The method of  claim 25 , wherein the expression level is determined by western blotting or immunohistochemistry. 
     
     
         28 . The method of  claim 24 , wherein the expression level is determined by RT-PCR, quantitive RT-PCR, expression array analysis, RNase protection assay or northern blotting.