{"doi":"10.1101/2024.11.11.623044","title":"Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state","abstract":"ABSTRACT The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ∼2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1 -mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1 -mutant lung cancer. Here we report a new mouse model of RIT1-driven lung cancer in which the human RIT1 M90I variant can be induced in a Cre-regulated manner. We show that autochthonous expression of RIT1 M90I in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1 M90I and inactivation of Nf2 drives an aggressive epithelial-to-mesenchymal (EMT) lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1-driven lung cancer in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target in RIT1 -mutant lung cancer. HIGHLIGHTS We report a new RIT1 M90I -mutant autochthonous lung tumor model The most common oncogenic variant of RIT1, RIT1 M90I , weakly promotes lung tumor development RIT1 M90I drives the formation of lethal lung tumors in cooperation with p53 and Nf2 tumor suppressor gene loss RIT1 M90I and YAP cooperatively regulate cJUN expression Therapeutic MEK and TEAD targeting suppresses RIT1 M90I -driven tumorigenesis","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":506002,"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":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":454749,"name":"Saksham Gupta","orcid":"0000-0002-7538-6345","position":1,"is_corresponding":false},{"id":580573,"name":"Sitapriya Moorthi","orcid":"0000-0001-6372-5170","position":2,"is_corresponding":false},{"id":84953,"name":"Maria McSharry","orcid":"0000-0001-5962-5441","position":3,"is_corresponding":false},{"id":563576,"name":"Shriya Kamlapurkar","orcid":"0000-0002-2686-3387","position":4,"is_corresponding":false},{"id":1144574,"name":"Siobhan O’Brien","orcid":"0000-0003-4958-1080","position":5,"is_corresponding":false},{"id":1068202,"name":"Annie Waldum","orcid":null,"position":6,"is_corresponding":false},{"id":84952,"name":"April Lo","orcid":"0000-0001-6128-9846","position":7,"is_corresponding":false},{"id":575469,"name":"Fujiko Duke","orcid":null,"position":8,"is_corresponding":false},{"id":1357331,"name":"Amy R. Lowe","orcid":null,"position":9,"is_corresponding":false},{"id":1109204,"name":"Elizabeth Cromwell","orcid":"0000-0003-1636-6691","position":10,"is_corresponding":false},{"id":956639,"name":"Raisa Glabman","orcid":"0000-0003-1492-8830","position":11,"is_corresponding":false},{"id":364431,"name":"Amanda Koehne","orcid":"0000-0002-1397-6964","position":12,"is_corresponding":false},{"id":79456,"name":"Alice H. Berger","orcid":"0000-0002-6538-2658","position":13,"is_corresponding":false},{"id":1357029,"name":"Marga B. Rominger","orcid":"0000-0003-2553-1687","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:10:50.984927Z","pmid":"39605726","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":[]}