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

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

doi:10.1016/j.ccell.2025.09.014

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Cancer Cell
DOIs	https://doi.org/10.1016/j.ccell.2025.09.014
State	Accepted/In press - 2025

Keywords

BRAF
cobimetinib
Erdheim-Chester disease
ERK
histiocytoses
Langerhans cell histiocytosis
macrophage
MEK
trametinib
ulixertinib

Access to Document

10.1016/j.ccell.2025.09.014

Cite this

Diamond, E. L., Emile, J. F., Fujino, T., Haroche, J., Maron, M. I., Lewis, A. M., Rahman, J., Reiner, A. S., Bossert, D., Rosenblum, M., Yabe, M., Petrova-Drus, K., Francis, J. H., Rotemberg, V., Rampal, R. K., Yoo, S., Daniyan, A. F., Mahajan, S., Hatzoglou, V., ... Durham, B. H. (Accepted/In press). RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition. Cancer Cell. https://doi.org/10.1016/j.ccell.2025.09.014

@article{c126106771344511a4a48344ad93b79e,

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 (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.",

keywords = "BRAF, cobimetinib, Erdheim-Chester disease, ERK, histiocytoses, Langerhans cell histiocytosis, macrophage, MEK, trametinib, ulixertinib",

author = "Diamond, \{Eli L.\} and Emile, \{Jean Francois\} and Takeshi Fujino and Julien Haroche and Maron, \{Maxim I.\} and Lewis, \{Alexander M.\} and Jahan Rahman and Reiner, \{Anne S.\} and Dana Bossert and Marc Rosenblum and Mariko Yabe and Kseniya Petrova-Drus and Francis, \{Jasmine H.\} and Veronica Rotemberg and Rampal, \{Raajit K.\} and Sarah Yoo and Daniyan, \{Anthony F.\} and Sonia Mahajan and Vaios Hatzoglou and Robert Young and Ulaner, \{Gary A.\} and Wiebke R{\"o}sler and Oshrat Hershkovitz-Rokah and Ofer Shpilberg and Mazor, \{Roei D.\} and Chen, \{Luke Y.C.\} and Michael Singer and Cuibus, \{M. Adriana\} 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 \{De Lassus\}, \{Laure Farnault\} and Neal Rosen and Omar Abdel-Wahab and Durham, \{Benjamin H.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

doi = "10.1016/j.ccell.2025.09.014",

language = "אנגלית",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

}

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 2025, 'RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition', Cancer Cell. https://doi.org/10.1016/j.ccell.2025.09.014

TY - JOUR

T1 - RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

AU - Diamond, Eli L.

AU - Emile, Jean Francois

AU - Fujino, Takeshi

AU - Haroche, Julien

AU - Maron, Maxim I.

AU - Lewis, Alexander M.

AU - Rahman, Jahan

AU - Reiner, Anne S.

AU - Bossert, Dana

AU - Rosenblum, Marc

AU - Yabe, Mariko

AU - Petrova-Drus, Kseniya

AU - Francis, Jasmine H.

AU - Rotemberg, Veronica

AU - Rampal, Raajit K.

AU - Yoo, Sarah

AU - Daniyan, Anthony F.

AU - Mahajan, Sonia

AU - Hatzoglou, Vaios

AU - Young, Robert

AU - Ulaner, Gary A.

AU - Rösler, Wiebke

AU - Hershkovitz-Rokah, Oshrat

AU - Shpilberg, Ofer

AU - Mazor, Roei D.

AU - Chen, Luke Y.C.

AU - Singer, Michael

AU - Cuibus, M. Adriana

AU - Weis, Kenyon

AU - Benbarche, Salima

AU - Zhang, Pu

AU - Fox, Nina

AU - Castro, Cynthia

AU - Tittley, Steven

AU - Witkowski, Matthew

AU - Cohen-Aubart, Fleur

AU - Terriou, Louis

AU - Hanoun, Maher

AU - Schleinitz, Nicolas

AU - Sosa, Gabriela

AU - Hautala, Timo

AU - De Lassus, Laure Farnault

AU - Rosen, Neal

AU - Abdel-Wahab, Omar

AU - Durham, Benjamin H.

PY - 2025

Y1 - 2025

N2 - 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.

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 (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.

KW - BRAF

KW - cobimetinib

KW - Erdheim-Chester disease

KW - ERK

KW - histiocytoses

KW - Langerhans cell histiocytosis

KW - macrophage

KW - MEK

KW - trametinib

KW - ulixertinib

UR - https://www.scopus.com/pages/publications/105020792988

U2 - 10.1016/j.ccell.2025.09.014

DO - 10.1016/j.ccell.2025.09.014

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 41135521

AN - SCOPUS:105020792988

SN - 1535-6108

JO - Cancer Cell

JF - Cancer Cell

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this