{"doi":"10.1101/2025.08.04.668444","title":"Genetic mechanisms of resistance to targeted KRAS inhibition","abstract":"ABSTRACT KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), yet the mechanisms of therapeutic resistance to KRAS inhibitors in these cancers remains poorly understood. Here, we deploy high-throughput CRISPR base editing screens to systematically map resistance mutations to three mechanistically distinct KRAS-targeted therapies, including KRAS-G12C(OFF) inhibitor (adagrasib), RAS(ON) G12C-selective tri-complex inhibitor (RMC-4998), and RAS(ON) multi-selective tri-complex inhibitor (RMC-7977). Using both a saturation Kras tiling approach and cancer-associated mutation library, we identify common and compound-selective second-site resistance mutations in Kras , as well as gain-of-function and loss-of-function variants across cancer-associated genes that rewire signaling networks in a context-dependent manner. Notably, we identify a recurrent missense mutation in capicua ( Cic ), that promotes resistance to RMC-7977 in vitro and in vivo. Moreover, we show that targeting NFκB signaling in CIC-mutant cells can resensitize them to RAS pathway inhibition and overcome resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558693,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"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":1459904,"name":"M.S. Kops","orcid":null,"position":1,"is_corresponding":false},{"id":1459905,"name":"Sara Bernardo","orcid":null,"position":2,"is_corresponding":false},{"id":846382,"name":"Henri Schmidt","orcid":"0000-0002-0132-3472","position":3,"is_corresponding":false},{"id":1459906,"name":"Elizabeth Grankowsky","orcid":null,"position":4,"is_corresponding":false},{"id":1459907,"name":"Adrian Vega","orcid":null,"position":5,"is_corresponding":false},{"id":1459505,"name":"Chen Zhang","orcid":"0000-0003-0622-6572","position":6,"is_corresponding":false},{"id":225130,"name":"Matthew J. Bott","orcid":"0000-0003-0523-4028","position":7,"is_corresponding":false},{"id":545344,"name":"Maria Skamagki","orcid":null,"position":8,"is_corresponding":false},{"id":1014876,"name":"Aidan C.A. Tomlinson","orcid":"0000-0002-9663-773X","position":9,"is_corresponding":false},{"id":1459506,"name":"Nicole A. Vita","orcid":"0000-0003-4985-6662","position":10,"is_corresponding":false},{"id":263587,"name":"Alyna Katti","orcid":"0000-0002-9662-965X","position":11,"is_corresponding":false},{"id":291417,"name":"Mark P. Labrecque","orcid":"0000-0001-7887-7599","position":12,"is_corresponding":false},{"id":1182501,"name":"Ida Aronchik","orcid":"0009-0002-1590-8778","position":13,"is_corresponding":false},{"id":333844,"name":"Mallika Singh","orcid":"0009-0003-0234-1589","position":14,"is_corresponding":false},{"id":237945,"name":"Lukas E. Dow","orcid":"0000-0001-7048-1418","position":15,"is_corresponding":false},{"id":292305,"name":"Bianca J. Diaz","orcid":"0000-0002-5309-1300","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40799582","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":[]}