Methods for determining responsiveness to mek/erk inhibitors

Abstract

A method for predicting the responsiveness of a cancer cell to an MEK inhibitor, comprising detecting the presence of at least one mutation in one or more genes selected from the group consisting of ADAM12, COL14A1, TNN, and TP53, in the cancer cell, by contacting a nucleic acid sample derived from the cancer cell with at least one oligonucleotide which allows specific detection of the mutation; wherein presence of mutation in ADAM12, COL14A1, TNN, TP53 and/or any combination thereof is indicative of decreased responsiveness of the cancer cell to the ERK inhibitor.

What is claimed is: 
     
         1 ) A method for treating a patient having cancer, comprising:
 obtaining a sample derived from the patient;   determining that the sample does not have a mutation in TP53 gene which results in Q331R, C135fs, E285K, V274F, Y220C, P250L, R175H, R248Q, R280K, R248L, C176Y, A307_splice, R273L, R158L, A138fs, H193R, A159D, C277F, R248W, Y220C, V274F, R196*, E224_splice, K164*, M246I, A159V, S241F, C242R, S261_splice, E339* in TP53 protein; and   administering an MEK inhibitor to the patient.   
     
     
         2 ) The method of  claim 1 , wherein the sample is a cancer cell or tissue derived from the patient. 
     
     
         3 ) The method of  claim 1 , wherein the MEK inhibitor is Trametinib. 
     
     
         4 ) The method of  claim 1 , wherein the determining step comprises amplifying at least a portion of the TP53 gene with an oligonucleotide as primer to generate an amplification product. 
     
     
         5 ) The method of  claim 1 , wherein the determining step comprises contacting the sample with an oligonucleotide which specifically hybridizes to the mutation of the TP53 gene to form a complex. 
     
     
         6 ) The method of  claim 1 , wherein the determining step involves an assay selected from the group consisting of sequencing, polymerase chain reaction (PCR), mass-spectrometric genotyping, HPLC, SSPC and a hybridization-based assay. 
     
     
         7 ) The method of  claim 1 , wherein the determining step further comprises determining if the patient has a second mutation in one or more genes selected from the group consisting of ADAM12, COL14A1 and TNN. 
     
     
         8 ) The method of  claim 7 , wherein the mutation in ADAM12 gene results in Q650K, R240L, C440Y, Q228E, H247D, M322I, T97fs, P168L or G308E in ADAM12 protein; wherein the mutation in COL14A1 gene results in R178W, L713 splice, Q1272K, L4791, L1295F, E1024K, P1467S, G737R, K1023T, G966C, S1512fs in COL14A1 protein; wherein the mutation in TNN gene results in V353M, Y296S, A733P, D707Y, D471Y, P1010T, S71L, D457Y, P1155L, R476C, Q872H, Q261L, D798Y, C1237*, D67N and T823S in TNN protein. 
     
     
         9 ) A method for treating a patient having cancer, comprising:
 obtaining a sample derived from the patient;   determining that the sample has a mutation in TP53 gene which results in Q331R, C135fs, E285K, V274F, Y220C, P250L, R175H, R248Q, R280K, R248L, C176Y, A307_splice, R273L, R158L, A138fs, H193R, A159D, C277F, R248W, Y220C, V274F, R196*, E224_splice, K164*, M246I, A159V, S241F, C242R, S261_splice, E339* in TP53 protein; and   administering a therapeutic agent to the patient, wherein the therapeutic agent is selected from the group consisting of a c-Met inhibitor, an agent targeting PI3K-Akt-mTOR signaling pathway, a chemotherapeutic agent, an anti-metabolite, an anti-hormonal agent, and an angiogenesis inhibitor.   
     
     
         10 ) The method of  claim 9 , wherein the sample is a cancer cell or tissue derived from the patient. 
     
     
         11 ) The method of  claim 9 , wherein the determining step comprises amplifying at least a portion of the TP53 gene with an oligonucleotide as primer to generate an amplification product. 
     
     
         12 ) The method of  claim 9 , wherein the determining step comprises contacting the sample with an oligonucleotide which specifically hybridizes to the mutation of the TP53 gene to form a complex. 
     
     
         13 ) The method of  claim 9 , wherein the determining step involves an assay selected from the group consisting of sequencing, polymerase chain reaction (PCR), mass-spectrometric genotyping, HPLC, SSPC and a hybridization-based assay. 
     
     
         14 ) The method of  claim 9 , wherein the determining step further comprises determining if the patient has a second mutation in one or more genes selected from the group consisting of ADAM12, COL14A1 and TNN. 
     
     
         15 ) The method of  claim 14 , wherein the mutation in ADAM12 gene results in Q650K, R240L, C440Y, Q228E, H247D, M322I, T97fs, P168L or G308E in ADAM12 protein; wherein the mutation in COL14A1 gene results in R178W, L713 splice, Q1272K, L4791, L1295F, E1024K, P1467S, G737R, K1023T, G966C, S1512fs in COL14A1 protein; wherein the mutation in TNN gene results in V353M, Y296S, A733P, D707Y, D471Y, P1010T, S71L, D457Y, P1155L, R476C, Q872H, Q261L, D798Y, C1237*, D67N and T823S in TNN protein.