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

Mundi, P. S., Grunn, A., Kojadinovic, A., Pampou, S., Karan, C., Realubit, R., Caescu, C. I., Hibshoosh, H., Aburi, M., Alvarez, M. J., et al.

10.1101/2025.10.12.681609 · was preprinted

biomedical

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Abstract

Treatment of gastrointestinal stromal tumor (GIST) with imatinib and other KIT-targeting drugs has improved outcomes significantly. 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--critical non-oncogene dependencies--in cancer cells. Unsupervised, MR-based clustering of 34 GIST patient tumor samples produced two clusters, one of which contained all imatinib-resistant tumors. Analysis of 9 single-cell RNA profiles of high-risk GIST revealed that tumors with clinical progression on imatinib harbored large subpopulations enriched for the MR-activity signature of imatinib-resistant tumors, while tumors with resistance-associated mutations but without overt progression showed smaller, variably sized enriched subpopulations. 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; selinexor and selumetinib were also effective compared to imatinib. We confirmed in vivo MR-activity reversal by these drugs, but not by ineffective drugs.

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biorxiv v2 2026-07-08 source ↗

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