{"doi":"10.1101/2020.07.03.187310","title":"An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer","abstract":"ABSTRACT Advances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR , and RIT1 . Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1 -mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1 M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1 -cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1 -mutant lung cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127012,"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":0.9508,"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":263366,"name":"Naomi T. Nkinsi","orcid":"0000-0002-0504-696X","position":1,"is_corresponding":false},{"id":575083,"name":"Amanda K. Riley","orcid":"0000-0002-5720-3269","position":2,"is_corresponding":false},{"id":337300,"name":"Phoebe C. R. Parrish","orcid":"0000-0002-3530-0105","position":3,"is_corresponding":false},{"id":575469,"name":"Fujiko Duke","orcid":null,"position":4,"is_corresponding":false},{"id":15880,"name":"Jenny Chen","orcid":"0000-0002-2992-4771","position":5,"is_corresponding":false},{"id":575470,"name":"Iris Fung","orcid":null,"position":6,"is_corresponding":false},{"id":263365,"name":"Jacqueline Watson","orcid":"0000-0002-4855-960X","position":7,"is_corresponding":false},{"id":107864,"name":"Matthew G. Rees","orcid":"0000-0002-2987-7581","position":8,"is_corresponding":false},{"id":291424,"name":"John K. Lee","orcid":"0000-0002-6570-2180","position":9,"is_corresponding":false},{"id":3750,"name":"Federica Piccioni","orcid":"0000-0003-1210-3210","position":10,"is_corresponding":false},{"id":575084,"name":"Emily M. Hatch","orcid":"0000-0002-3393-4075","position":11,"is_corresponding":false},{"id":79456,"name":"Alice H. Berger","orcid":"0000-0002-6538-2658","position":12,"is_corresponding":false},{"id":575082,"name":"Athea Vichas","orcid":"0000-0001-6328-6200","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-18T23:15:27.226519Z","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":[]}