RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

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<sup>E102_I103del</sup>) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1<sup>E102_I103del</sup>-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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Publication Details

Journal
Cancer Cell
Published
2025-10-23
DOI
https://doi.org/10.1016/j.ccell.2025.09.014
Citations
1
Primary Topic
Histiocytic Disorders and Treatments
Type
article
Field-Weighted Citation Impact
1.16
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article

RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

Jasmine H. Francis, Nina Fox, Dana Bossert, Robert J. Young et al.
1 citations
Cancer Cell
Histiocytic Disorders and Treatments
1.16
article

RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

Jasmine H. Francis, Nina Fox, Dana Bossert, Robert J. Young, Kseniya Petrova‐Drus, Maxim I. Maron, Gary A. Ulaner, Omar Abdel‐Wahab, Fleur Cohen‐Aubart, Steven Tittley, Karsten Weis, Michael Singer, N. Schleinitz, Vaios Hatzoglou, Matthew T. Witkowski, Benjamin H. Durham, Anne S. Reiner, Salima Benbarche, Cynthia Aparecida de Castro, Anthony F. Daniyan, Wiebke Rösler, Louis Terriou, T Fujino, Ofer Shpilberg, Pu Zhang, Neal Rosen, Luke Y. C. Chen, Sarah Yoo, Marc K. Rosenblum, Jean‐François Emile, Sonia Mahajan, Timo Hautala, Jahan Rahman, Raajit K. Rampal, Maher Hanoun, Roei David Mazor, M. Adriana Cuibus, Eli L. Diamond, Veronica Rotemberg, Oshrat Hershkovitz‐Rokah, Mariko Yabe, Gabriela Alejandra Sosa, Alexander M. Lewis, Julien Haroche, Laure Farnault De Lassus
article en
1 citations

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<sup>E102_I103del</sup>) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1<sup>E102_I103del</sup>-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.

Cancer CellVol. 44(1)
Dalhousie University (CA), Memorial Sloan Kettering Cancer Center (US), Inserm (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Assuta Medical Center (IL), Sorbonne Université (FR), Kettering University (US), Hôpital de la Conception (FR), Assistance Publique – Hôpitaux de Paris (FR), University Hospital of Zurich (CH), Pitié-Salpêtrière Hospital (FR), Hôpital Ambroise-Paré (FR), Hôpital Claude Huriez (FR), Hoag Orthopedic Institute (US), Fundacion Allende (AR), University of Colorado Anschutz Medical Campus (US), Ariel University (IL), University of Duisburg-Essen (DE), Oulu University of Applied Sciences (FI), University of Oulu (FI)
Openalex Percentile: Top 17%
Histiocytic Disorders and Treatments
1.16
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