Correlation of gastrointestinal stromal tumor (GIST) gene expression signatures and response to imatinib mesylate in the Radiation Therapy Oncology Group phase II clinical trial S-0132

Abstract

10533 Background: Despite the known efficacy of imatinib mesylate (IM) in metastatic GIST, both primary and secondary drug resistance remain a clinical problem. Therefore, future management of GIST may benefit from further molecular characterization associated with IM treatment. Methods: A recently completed prospective phase II trial of neoadjuvant/adjuvant IM treatment for advanced primary and recurrent operable GISTs included gene expression profiling using oligonucleotide microarrays on tumor samples obtained before and after neoadjuvant IM therapy for 8 to 12 weeks. Fifty-two analyzable patients were classified according to changes in tumor size after IM based on CT scan measurements. A response was defined as >25% tumor reduction. Gene profiling data were then evaluated with SAM analysis (FDR = 10%) to identify differentially expressed genes (in pre-treatment GIST samples). In addition, a custom siRNA library was designed targeting these genes and a mid-throughput siRNA synthetic lethal screening approach was used to evaluate the ability of each to sensitize GIST cells to IM. Results: Thirty-eight genes were expressed at significantly lower levels in the pre-treatment samples of tumors that rapidly responded to IM. Eighteen of these genes encoded KRAB domain containing zinc finger (KRAB-ZNF) transcriptional repressors. Importantly, ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset of these predicted likely response to IM-based therapy in a naïve panel of GISTs. Further evaluation revealed that modifying in vitroexpression of genes via RNAi approaches within this predictive response signature enhanced the sensitivity of GIST cells to IM. Conclusions: Using clinical samples from a prospective neoadjuvant/adjuvant phase II trial we have identified a genetic signature which includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely rapid response to short-term IM treatment and which may provide a prognostic biomarker identifying patients who will benefit from it. [Table: see text]