{"doi":"10.1101/2025.10.12.681609","title":"Systematic elucidation and pharmacologic targeting of non-oncogene dependencies in imatinib-resistant gastrointestinal stromal tumor","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577849,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9436,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":809455,"name":"Adina Grunn","orcid":"0009-0006-7810-4450","position":1,"is_corresponding":false},{"id":1487276,"name":"Arsenije Kojadinovic","orcid":"0000-0003-1199-7136","position":2,"is_corresponding":false},{"id":465009,"name":"Charles Karan","orcid":"0000-0003-4012-8677","position":3,"is_corresponding":false},{"id":465008,"name":"Ronald Realubit","orcid":"0000-0001-7072-0810","position":5,"is_corresponding":false},{"id":809459,"name":"Cristina I. Caescu","orcid":"0000-0003-4200-2779","position":6,"is_corresponding":false},{"id":69823,"name":"Hanina Hibshoosh","orcid":"0000-0001-9688-4514","position":7,"is_corresponding":false},{"id":574849,"name":"Mahalaxmi Aburi","orcid":"0009-0008-8559-4536","position":8,"is_corresponding":false},{"id":347862,"name":"Mariano J. Alvarez","orcid":"0000-0002-7503-2491","position":9,"is_corresponding":false},{"id":560392,"name":"Matthew Ingham","orcid":"0000-0002-5518-8413","position":10,"is_corresponding":false},{"id":1487277,"name":"Denisse Evans","orcid":"0000-0002-3953-1066","position":11,"is_corresponding":false},{"id":1487278,"name":"Sara Rothschild","orcid":"0000-0001-6602-3924","position":12,"is_corresponding":false},{"id":241729,"name":"Gary K. Schwartz","orcid":"0000-0003-1813-5061","position":13,"is_corresponding":false},{"id":19046,"name":"Andrea Califano","orcid":"0000-0003-4742-3679","position":14,"is_corresponding":false},{"id":574846,"name":"Prabhjot S. Mundi","orcid":"0000-0001-9871-4463","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T02:58:16.148027Z","pmid":"41278727","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}