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. Statement of SignificanceWe leveraged our network-based platforms, OncoTreat and OncoTarget, to characterize Master Regulators of imatinib-resistance in GIST and identify candidate MR-targeting drugs, an unmet clinical need. Top predicted drugs were successfully validated in cognate PDXs, thus providing a path for translation.