Mutations in KIT confer imatinib resistance in gastrointestinal stromal tumors
View Patent ↗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. A method of screening an individual for imatinib resistance or a predisposition thereto, wherein the individual has a cancer characterized by having at least one cell comprising a c-KIT polynucleotide, the method comprising determining the presence of a T->C mutation at nucleotide position 1982 of the KIT gene, said nucleotide position defined according to the KIT gene nucleotide sequence of SEQ ID NO:29, in a sample obtained from the cancer of said individual, wherein the presence of such a mutation indicates the individual exhibits imatinib resistance or a predisposition thereto.
2. The method of claim 1 , wherein the cancer is a gastrointestinal stromal tumor or a metastasis thereof.
3. The method of claim 1 , wherein the sample from the individual is comprised in paraffin or is frozen.
4. The method of claim 1 , wherein the sample from the individual comprises fluid, cell, tissue, or a combination thereof.
5. The method of claim 1 , wherein the determining the presence of the mutation is further defined as assaying said sample by a polymerase chain reaction using one or more polynucleotide primers.
6. The method of claim 5 , wherein the polymerase chain reaction is small-pool polymerase chain reaction.
7. The method of claim 5 , wherein the polymerase chain reaction utilizes a primer that would amplify a polynucleotide sequence comprising the mutation or a complement thereof.
8. The method of claim 1 , further defined as assaying RNA for the mutation.
9. The method of claim 1 , further defined as assaying the KIT gene for the mutation.
10. The method of claim 1 , wherein the cancer is an ovarian cancer.
11. The method of claim 5 , wherein the one or more polynucleotide primers are associated with a substrate.
12. The method of claim 11 , wherein the substrate is a microchip.