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.
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BibTeX
@article{diamond2026rafindependent,
title = {{RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition}},
author = {Eli L. Diamond and Jean-Francois Emile and Takeshi Fujino and Julien Haroche and Maxim I. Maron and Alexander M. Lewis and Jahan Rahman and Anne S. Reiner and Dana Bossert and Marc Rosenblum and Mariko Yabe and Kseniya Petrova-Drus and Jasmine H. Francis and Veronica Rotemberg and Raajit K. Rampal and Sarah Yoo and Anthony F. Daniyan and Sonia Mahajan and Vaios Hatzoglou and Robert Young and Gary A. Ulaner and Wiebke Rösler and Oshrat Hershkovitz-Rokah and Ofer Shpilberg and Roei D. Mazor and Luke Y.C. Chen and Michael Singer and M. Adriana Cuibus and Kenyon Weis and Salima Benbarche and Pu Zhang and Nina Fox and Cynthia Castro and Steven Tittley and Matthew Witkowski and Fleur Cohen-Aubart and Louis Terriou and Maher Hanoun and Nicolas Schleinitz and Gabriela Sosa and Timo Hautala and Laure Farnault de Lassus and Neal Rosen and Omar Abdel-Wahab and Benjamin H. Durham},
journal = {Cancer Cell},
year = {2026},
month = nov,
doi = {10.1016/j.ccell.2025.09.014},
url = {https://hal.science/hal-05851906v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition
AU - Eli L. Diamond
AU - Jean-Francois Emile
AU - Takeshi Fujino
AU - Julien Haroche
AU - Maxim I. Maron
AU - Alexander M. Lewis
AU - Jahan Rahman
AU - Anne S. Reiner
AU - Dana Bossert
AU - Marc Rosenblum
AU - Mariko Yabe
AU - Kseniya Petrova-Drus
AU - Jasmine H. Francis
AU - Veronica Rotemberg
AU - Raajit K. Rampal
AU - Sarah Yoo
AU - Anthony F. Daniyan
AU - Sonia Mahajan
AU - Vaios Hatzoglou
AU - Robert Young
AU - Gary A. Ulaner
AU - Wiebke Rösler
AU - Oshrat Hershkovitz-Rokah
AU - Ofer Shpilberg
AU - Roei D. Mazor
AU - Luke Y.C. Chen
AU - Michael Singer
AU - M. Adriana Cuibus
AU - Kenyon Weis
AU - Salima Benbarche
AU - Pu Zhang
AU - Nina Fox
AU - Cynthia Castro
AU - Steven Tittley
AU - Matthew Witkowski
AU - Fleur Cohen-Aubart
AU - Louis Terriou
AU - Maher Hanoun
AU - Nicolas Schleinitz
AU - Gabriela Sosa
AU - Timo Hautala
AU - Laure Farnault de Lassus
AU - Neal Rosen
AU - Omar Abdel-Wahab
AU - Benjamin H. Durham
PY - 2026
DA - 2026/11/04
JO - Cancer Cell
DO - 10.1016/j.ccell.2025.09.014
UR - https://hal.science/hal-05851906v1
AB - 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.
SN - 1878-3686
ER -