Mutations in Kit Confer Imatinib Resistance in Gastrointestinal Stromal Tumors

Abstract

The present invention relates to methods and compositions concerning resistance to a drug for cancer comprising aberrant KIT signal, such as aberrant KIT sequence or expression. In a specific embodiment, the cancer is also initially responsive to imatinib therapy, such as in gastrointestinal stromal tumors (GISTs). In particular embodiments, a mutation in a KIT polynucleotide confers resistance to imatinib treatment, and in specific embodiments the exemplary mutation is at 1982T→C. Thus, the invention provides a means to adjust for or circumvent the resistance to imatinib drug treatment.

1 . An isolated human KIT polynucleotide comprising a mutation at 1982T, as exemplified by SEQ ID NO:29. 
     
     
         2 . The polynucleotide of  claim 1 , further defined as a 1982T→C mutation. 
     
     
         3 . The polynucleotide of  claim 1 , further defined as being comprised in a vector. 
     
     
         4 . The polynucleotide of  claim 1 , further defined as being associated with a substrate. 
     
     
         5 . The polynucleotide of  claim 4 , wherein said substrate is a microchip. 
     
     
         6 . The polynucleotide of  claim 1 , further defined as being comprised in a cell. 
     
     
         7 .- 25 . (canceled) 
     
     
         26 . A kit for identifying a drug resistance-conferring mutation, said kit in a suitable container and comprising at least one of the following:
 a wild-type KIT polynucleotide;   at least one KIT polynucleotide comprising a drug resistance-conferring mutation; or   a primer that identifies the resistance-conferring mutation, wherein the drug resistance-conferring mutation is at nucleotide 1982 of the KIT gene, as exemplified by SEQ ID NO:29.   
     
     
         27 - 31 . (canceled) 
     
     
         32 . A KIT primer, comprising sequence, or the complement thereof, that is indicative of conferring resistance to imatinib, wherein the resistance-conferring mutation is at nucleotide 1982 of the KIT gene, as exemplified by SEQ ID NO:29. 
     
     
         33 . (canceled) 
     
     
         34 . The primer of  claim 32 , wherein the nucleotide 1982 is at the 3′ end of the primer. 
     
     
         35 . (canceled)