Despite initial efficacy of
imatinib mesylate in most
gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of
tumors before and after
imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant
imatinib mesylate treatment for advanced primary and recurrent operable GISTs (
Radiation Therapy Oncology Group S0132), gene expression profiling using
oligonucleotide microarrays was done on
tumor samples obtained before and after
imatinib mesylate therapy. Patients were classified according to changes in
tumor size
after treatment based on computed tomography scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays to identify differentially expressed genes (in pretreatment GIST samples). Based on Statistical Analysis of Microarrays [False Discovery Rate (FDR), 10%], 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from
tumors that significantly responded to 8 to 12 weeks of
imatinib mesylate, that is, >25%
tumor reduction. Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Importantly, 10 KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to
imatinib mesylate-based
therapy in a naïve panel of GIST. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to
imatinib mesylate. Using clinical pretreatment biopsy samples from a prospective neoadjuvant phase II trial, we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term
imatinib mesylate treatment.