Systematic elucidation and pharmacologic targeting on non-oncogene dependencies in imatinib-resistant gastrointestinal stromal tumor

Treatment of gastrointestinal stromal tumor (GIST) with imatinib and other KIT-targeting drugs, has been effective. However, most patients with advanced GIST eventually develop imatinib-resistance and succumb to disease. We have developed mutation-agnostic, network-based methodologies to systematically elucidate and pharmacologically target Master Regulator (MR) proteins representing critical non-oncogene dependencies of cancer cells. Unsupervised, MR-based clustering of 34 GIST patient tumor samples produced two clusters clearly separating imatinib-resistant vs. sensitive tumors. High-throughput profiling of transcriptional responses by two GIST cell lines to FDA approved and late-stage experimental drugs identified six candidate drugs that reversed the MR activity of imatinib-resistant GIST. Predictions were validated in two imatinib-resistant, patient-derived xenograft (PDX) models. The top prediction, linifanib, induced marked tumor growth inhibition in both PDXs across a wide dose range, while selinexor was also effective compared to imatinib. We confirmed in vivo MR activity reversal by these drugs, but not by ineffective drugs.