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Ref Type Journal Article
PMID (41135521)
Authors Diamond EL, Emile JF, Fujino T, Haroche J, Maron MI, Lewis AM, Rahman J, Reiner AS, Bossert D, Rosenblum M, Yabe M, Petrova-Drus K, Francis JH, Rotemberg V, Rampal RK, Yoo S, Daniyan AF, Mahajan S, Hatzoglou V, Young R, Ulaner GA, Rösler W, Hershkovitz-Rokah O, Shpilberg O, Mazor RD, Chen LYC, Singer M, Cuibus MA, Weis K, Benbarche S, Zhang P, Fox N, Castro C, Tittley S, Witkowski M, Cohen-Aubart F, Terriou L, Hanoun M, Schleinitz N, Sosa G, Hautala T, De Lassus LF, Rosen N, Abdel-Wahab O, Durham BH
Title RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 44 1 2026 Jan 12 203-220.e8 Cancer Cell
URL
Abstract Text 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 (MEK1E102_I103del) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1E102_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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 E102_I103del histiocytosis predicted - sensitive Ulixertinib Case Reports/Case Series Actionable In a clinical case study, Ulixertinib (BVD-523) treatment resulted in 2 partial responses and 2 complete responses among 4 patients with histiocytosis, including Erdheim-chester disease and Langerhans cell histiocytosis, harboring MAP2K1 E102_I103del (PMID: 41135521). 41135521