{"doi":"10.1172/jci147849","title":"RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics","abstract":"Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.","journal":"Journal of Clinical Investigation","year":2021,"id":166392,"datarank":0.5333022092234121,"base_score":3.5553480614894135,"endowment":3.5553480614894135,"self_citation_contribution":0.5333022092234121,"citation_network_contribution":0.0,"self_endowment_contribution":0.5333022092234121,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":34,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":692922,"name":"Amruta S. Samant","orcid":null,"position":1,"is_corresponding":false},{"id":298776,"name":"Amin H. Nassar","orcid":"0000-0002-8084-9105","position":2,"is_corresponding":false},{"id":486929,"name":"Jonathan So","orcid":"0000-0001-9919-2476","position":3,"is_corresponding":false},{"id":692923,"name":"Elizabeth P. Garcia","orcid":null,"position":4,"is_corresponding":false},{"id":692924,"name":"Catherine R. Curran","orcid":null,"position":5,"is_corresponding":false},{"id":351741,"name":"Justin H. Hwang","orcid":"0000-0003-1686-7103","position":6,"is_corresponding":false},{"id":486928,"name":"David L. Mayhew","orcid":"0000-0001-9127-0548","position":7,"is_corresponding":false},{"id":558516,"name":"Anwesha Nag","orcid":"0000-0002-1947-7429","position":8,"is_corresponding":false},{"id":55261,"name":"Aaron R. Thorner","orcid":"0000-0002-9160-7881","position":9,"is_corresponding":false},{"id":692925,"name":"Judit Börcsök","orcid":null,"position":10,"is_corresponding":false},{"id":691987,"name":"Zsofia Sztupinszki","orcid":"0000-0002-8691-4086","position":11,"is_corresponding":false},{"id":381830,"name":"Chong-xian Pan","orcid":"0000-0002-8588-3994","position":12,"is_corresponding":false},{"id":235727,"name":"Joaquim Bellmunt","orcid":"0000-0003-2328-3421","position":13,"is_corresponding":false},{"id":298782,"name":"David J. Kwiatkowski","orcid":"0000-0002-5668-5219","position":14,"is_corresponding":false},{"id":274683,"name":"Guru Sonpavde","orcid":"0000-0002-1010-9611","position":15,"is_corresponding":false},{"id":418,"name":"Eliezer M. Van Allen","orcid":"0000-0002-0201-4444","position":16,"is_corresponding":false},{"id":323944,"name":"Kent W. Mouw","orcid":"0000-0001-7939-7343","position":17,"is_corresponding":false},{"id":692921,"name":"Raie T. Bekele","orcid":null,"position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:45:49.644768Z","pmid":"34554931","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":[]}