Mutations in the bcr-abl tyrosine kinase associated with resistance to sti-571

Abstract

The invention described herein relates to novel genes and their encoded proteins, termed Mutants Associated with Resistance to STI-571 (e.g., T315I Bcr-Abl), and to diagnostic and therapeutic methods and compositions useful in the management of various cancers that express MARS. The invention further provides methods for identifying molecules that bind to and/or modulate the functional activity of MARS.

1 - 50 . (canceled) 
     
     
         51 . A method of detecting the presence of a cancer cell that is resistant to treatment with a tyrosine kinase inhibitor in a sample from an individual, the method comprising:
 (a) obtaining a sample from the individual; and   (b) detecting a mutation in a Bcr-Abl polypeptide in the sample at the amino acid position corresponding to amino acid position 315 of SEQ ID NO: 1 by determining the nucleotide sequence of at least the codon encoding the amino acid residue of the Bcr-Abl polypeptide at the position corresponding to amino acid position 315 of SEQ ID NO: 1, wherein the presence of a mutation indicates that the sample contains a cancer cell that is resistant to treatment with a tyrosine kinase inhibitor.   
     
     
         52 . The method of  claim 51 , wherein the determining comprises a reverse transcriptase polymerase chain reaction. 
     
     
         53 . The method of  claim 51 , wherein the determining comprises DNA sequencing. 
     
     
         54 . The method of  claim 51 , wherein the cancer cell is a leukemia cell. 
     
     
         55 . The method of  claim 54 , wherein the leukemia is myelogenous leukemia. 
     
     
         56 . The method of  claim 51 , wherein the mutation is an isoleucine at the amino acid position in the Bcr-Abl polypeptide corresponding to position 315 of SEQ ID NO: 1. 
     
     
         57 . The method of  claim 56 , wherein the determined nucleotide sequence of at least the codon encoding the amino acid residue of the Bcr-Abl polypeptide at the position corresponding to amino acid position 315 of SEQ ID NO: 1 comprises a C to T point mutation compared to the nucleotide codon encoding amino acid position 315 of SEQ ID NO: 1, wherein the point mutation results in the isoleucine at position 315 of SEQ ID NO: 1. 
     
     
         58 . The method of  claim 51 , wherein the sample is obtained from blood, bone marrow or cancer cells. 
     
     
         59 . The method of  claim 51 , wherein the method of detecting further comprises comparing the amino acid residue at amino acid position 315 of SEQ ID NO: 1 with the amino acid residue encoded by the codon whose nucleotide sequence is determined. 
     
     
         60 . The method of  claim 51 , wherein the individual is undergoing tyrosine kinase inhibitor therapy prior to clinical relapse. 
     
     
         61 . The method according to  claim 61 , wherein the method further comprises determining a therapeutic regimen for the individual, wherein the therapeutic regimen does not comprise administration of STI-571 if the mutation is detected. 
     
     
         62 . The method according to  claim 61 , wherein the method further comprises administering the therapeutic regimen to the individual. 
     
     
         63 . The method according to  claim 62 , wherein the therapeutic regimen comprises allogeneic stem cell transplantation. 
     
     
         64 . The method according to  claim 62 , wherein the therapeutic regiment comprises administration of a tyrosine kinase inhibitor that is not STI-571. 
     
     
         65 . The method according to  claim 64 , wherein the tyrosine kinase inhibitor inhibits a Bcr-Abl polypeptide that comprises a mutation at the amino acid position corresponding to amino acid position 315 of SEQ ID NO: 1. 
     
     
         66 . The method according to  claim 65 , wherein the tyrosine kinase inhibitor inhibits a src kinase. 
     
     
         67 . The method according to  claim 65 , wherein the tyrosine kinase inhibitor inhibits one or more of PDGFR, EGFR and VEGFR. 
     
     
         68 . The method according to  claim 65 , wherein the tyrosine kinase inhibitor inhibits a src kinase and one or more of PDGFR, EGFR and VEGFR. 
     
     
         69 . A method comprising:
 (a) obtaining a sample comprising a cancer cell from an individual; and   (b) detecting a mutation in a Bcr-Abl polypeptide in the sample at the amino acid position corresponding to amino acid position 315 of SEQ ID NO: 1 by determining the nucleotide sequence of at least the codon encoding the amino acid residue of the Bcr-Abl polypeptide at the position corresponding to amino acid position 315 of SEQ ID NO: 1.   
     
     
         70 . The method of  claim 69 , wherein the mutation is an isoleucine at the amino acid position in the Bcr-Abl polypeptide corresponding to position 315 of SEQ ID NO: 1.