{"doi":"10.1101/2020.10.26.356352","title":"Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in <i>EGFR</i> mutant lung cancer","abstract":"Abstract Molecularly targeted cancer therapy has improved outcomes for cancer patients with targetable oncoproteins, such as mutant epidermal growth factor receptor ( EGFR ) in lung cancer. Yet, long-term patient survival remains limited because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations in the EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR . Here, we report the functional impact of inactivating genetic alteration of the mRNA splicing factor RBM10 that co-occur with mutant EGFR . RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of Bcl-xS-(pro-apoptotic)-to-Bcl-xL(anti-apoptotic) Bcl-x isoforms. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Co-inhibition of Bcl-xL and mutant EGFR overcame resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations, and on the impact of splicing factor deficiency in the modulation of sensitivity to targeted kinase inhibitor cancer therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127548,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3210,"name":"Wei Wu","orcid":"0000-0002-6556-067X","position":1,"is_corresponding":false},{"id":576853,"name":"Niki Karachaliou","orcid":"0000-0002-2378-0498","position":2,"is_corresponding":false},{"id":3220,"name":"Collin M. Blakely","orcid":"0000-0001-8134-3651","position":3,"is_corresponding":false},{"id":557730,"name":"Junji Suzuki","orcid":"0000-0003-1648-5471","position":4,"is_corresponding":false},{"id":258754,"name":"Siraj M. Ali","orcid":"0000-0001-7477-4023","position":5,"is_corresponding":false},{"id":3209,"name":"D. Lucas Kerr","orcid":"0000-0002-0557-8341","position":6,"is_corresponding":false},{"id":577838,"name":"Victor Olivas","orcid":null,"position":7,"is_corresponding":false},{"id":577839,"name":"Jonathan Shue","orcid":null,"position":8,"is_corresponding":false},{"id":492216,"name":"Julia Rotow","orcid":"0000-0003-4547-2960","position":9,"is_corresponding":false},{"id":555255,"name":"Manasi K. Mayekar","orcid":null,"position":10,"is_corresponding":false},{"id":554540,"name":"Franziska Haderk","orcid":"0000-0001-9658-2778","position":11,"is_corresponding":false},{"id":576854,"name":"Nilanjana Chatterjee","orcid":"0000-0002-1203-5222","position":12,"is_corresponding":false},{"id":310704,"name":"Anatoly Urisman","orcid":"0000-0001-8364-5303","position":13,"is_corresponding":false},{"id":453660,"name":"Yuriy Kirichok","orcid":"0000-0001-7155-843X","position":14,"is_corresponding":false},{"id":545854,"name":"Daniel S.W. Tan","orcid":"0000-0002-6514-6786","position":15,"is_corresponding":false},{"id":90047,"name":"R. Rosell","orcid":"0000-0003-0817-3400","position":16,"is_corresponding":false},{"id":552244,"name":"Ross A. Okimoto","orcid":"0000-0002-4467-8476","position":17,"is_corresponding":false},{"id":3224,"name":"Trever G. Bivona","orcid":"0000-0001-5734-4128","position":18,"is_corresponding":false},{"id":552245,"name":"Shigeki Nanjo","orcid":"0000-0001-8356-9849","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:15:34.966380Z","pmid":null,"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":[]}