{"doi":"10.1016/j.ccell.2025.09.014","title":"RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition","abstract":"Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1 E102_I103del ) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1 E102_I103del -mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo , identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses. • RAF-independent (class III) MEK1 mutations are common in histiocytoses patients • Class III MEK1/2 mutations are associated with MEK inhibitor disease progression • Class III MEK1 E102_I103del mutation drives aggressive myeloid neoplasms in mice • Class III MEK1-mutant histiocytoses patients and mice respond to ERK inhibition Diamond et al. find RAF-independent (“class III”) mutations in MEK1/2 kinases are common in patients with systemic histiocytic neoplasms, drive disease in a conditional knock-in mouse model, and associate with progression on FDA-approved MEK inhibitors. Patients with these mutations who progress on MEK inhibitors respond to the ERK inhibitor ulixertinib.","journal":"Cancer Cell","year":2025,"id":527283,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"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":430504,"name":"Jean‐François Emile","orcid":"0000-0002-6073-4466","position":1,"is_corresponding":false},{"id":1297258,"name":"T Fujino","orcid":"0000-0003-3444-4198","position":2,"is_corresponding":false},{"id":430498,"name":"Julien Haroche","orcid":"0009-0003-9794-1316","position":3,"is_corresponding":false},{"id":247700,"name":"Maxim I. Maron","orcid":"0000-0001-7809-5888","position":4,"is_corresponding":false},{"id":638611,"name":"Alexander M. Lewis","orcid":"0000-0001-8003-9535","position":5,"is_corresponding":false},{"id":557773,"name":"Jahan Rahman","orcid":"0000-0001-8755-5890","position":6,"is_corresponding":false},{"id":288021,"name":"Anne S. Reiner","orcid":"0000-0002-1258-6112","position":7,"is_corresponding":false},{"id":502031,"name":"Dana Bossert","orcid":null,"position":8,"is_corresponding":false},{"id":236602,"name":"Marc K. Rosenblum","orcid":"0000-0002-0530-0155","position":9,"is_corresponding":false},{"id":55984,"name":"Mariko Yabe","orcid":"0000-0002-3864-7921","position":10,"is_corresponding":false},{"id":275369,"name":"Kseniya Petrova‐Drus","orcid":"0000-0002-4048-8376","position":11,"is_corresponding":false},{"id":319965,"name":"Jasmine H. Francis","orcid":"0000-0002-7637-3108","position":12,"is_corresponding":false},{"id":620922,"name":"Veronica Rotemberg","orcid":"0000-0003-0639-2677","position":13,"is_corresponding":false},{"id":259770,"name":"Raajit K. Rampal","orcid":"0000-0002-0355-6368","position":14,"is_corresponding":false},{"id":604714,"name":"Sarah Yoo","orcid":"0009-0000-8418-0843","position":15,"is_corresponding":false},{"id":268587,"name":"Anthony F. Daniyan","orcid":"0009-0002-2742-2281","position":16,"is_corresponding":false},{"id":336916,"name":"Sonia Mahajan","orcid":"0000-0002-2625-4418","position":17,"is_corresponding":false},{"id":255796,"name":"Vaios Hatzoglou","orcid":"0000-0003-0252-0694","position":18,"is_corresponding":false},{"id":281410,"name":"Robert J. Young","orcid":"0000-0001-7003-3017","position":19,"is_corresponding":false},{"id":235767,"name":"Gary A. Ulaner","orcid":"0000-0002-7953-0113","position":20,"is_corresponding":false},{"id":1403963,"name":"Wiebke Rösler","orcid":"0000-0003-0495-1674","position":21,"is_corresponding":false},{"id":430508,"name":"Oshrat Hershkovitz‐Rokah","orcid":"0000-0003-4685-0679","position":22,"is_corresponding":false},{"id":430507,"name":"Ofer Shpilberg","orcid":"0000-0003-4463-7647","position":23,"is_corresponding":false},{"id":430505,"name":"Roei David Mazor","orcid":"0000-0002-4784-9808","position":24,"is_corresponding":false},{"id":252163,"name":"Luke Y. C. Chen","orcid":"0000-0002-9551-2951","position":25,"is_corresponding":false},{"id":620120,"name":"Michael Singer","orcid":"0000-0001-9941-7217","position":26,"is_corresponding":false},{"id":1143128,"name":"M. Adriana Cuibus","orcid":null,"position":27,"is_corresponding":false},{"id":1404598,"name":"Kenyon Weis","orcid":null,"position":28,"is_corresponding":false},{"id":638299,"name":"Salima Benbarche","orcid":"0000-0001-5314-0435","position":29,"is_corresponding":false},{"id":1041710,"name":"Pu Zhang","orcid":"0000-0002-1548-2087","position":30,"is_corresponding":false},{"id":740444,"name":"Nina Fox","orcid":null,"position":31,"is_corresponding":false},{"id":1060872,"name":"Cynthia Aparecida de Castro","orcid":"0000-0002-2675-8069","position":32,"is_corresponding":false},{"id":854395,"name":"Steven Tittley","orcid":"0000-0002-0579-4212","position":33,"is_corresponding":false},{"id":247435,"name":"Matthew T. Witkowski","orcid":"0000-0003-1434-4288","position":34,"is_corresponding":false},{"id":638472,"name":"Fleur Cohen‐Aubart","orcid":"0000-0002-7610-4995","position":35,"is_corresponding":false},{"id":1403964,"name":"Louis Terriou","orcid":"0000-0001-5919-9956","position":36,"is_corresponding":false},{"id":1403965,"name":"Maher Hanoun","orcid":"0000-0002-1754-8940","position":37,"is_corresponding":false},{"id":1403966,"name":"N. Schleinitz","orcid":"0000-0001-9449-3392","position":38,"is_corresponding":false},{"id":1404599,"name":"Gabriela Alejandra Sosa","orcid":null,"position":39,"is_corresponding":false},{"id":1028491,"name":"Timo Hautala","orcid":"0000-0001-7889-1614","position":40,"is_corresponding":false},{"id":1404600,"name":"Laure Farnault De Lassus","orcid":null,"position":41,"is_corresponding":false},{"id":227117,"name":"Neal Rosen","orcid":"0000-0002-8307-654X","position":42,"is_corresponding":false},{"id":75043,"name":"Omar Abdel-Wahab","orcid":"0000-0002-3907-6171","position":43,"is_corresponding":false},{"id":297431,"name":"Benjamin H. Durham","orcid":"0000-0001-8090-5448","position":44,"is_corresponding":false},{"id":267976,"name":"Eli L. Diamond","orcid":"0000-0001-5456-5961","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41135521","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":[]}