2. Academic Validation
  3. RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

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

  • Cancer Cell. 2025 Oct 23:S1535-6108(25)00406-4. doi: 10.1016/j.ccell.2025.09.014.
Eli L Diamond 1,  Jean-Francois Emile 2,  Takeshi Fujino 3,  Julien Haroche 4,  Maxim I Maron 3,  Alexander M Lewis 3,  Jahan Rahman 3,  Anne S Reiner 5,  Dana Bossert 1,  Marc Rosenblum 6,  Mariko Yabe 6,  Kseniya Petrova-Drus 6,  Jasmine H Francis 7,  Veronica Rotemberg 8,  Raajit K Rampal 9,  Sarah Yoo 9,  Anthony F Daniyan 9,  Sonia Mahajan 10,  Vaios Hatzoglou 10,  Robert Young 10,  Gary A Ulaner 11,  Wiebke Rösler 12,  Oshrat Hershkovitz-Rokah 13,  Ofer Shpilberg 14,  Roei D Mazor 15,  Luke Y C Chen 16,  Michael Singer 3,  M Adriana Cuibus 3,  Kenyon Weis 3,  Salima Benbarche 3,  Pu Zhang 3,  Nina Fox 3,  Cynthia Castro 3,  Steven Tittley 3,  Matthew Witkowski 17,  Fleur Cohen-Aubart 4,  Louis Terriou 18,  Maher Hanoun 19,  Nicolas Schleinitz 20,  Gabriela Sosa 21,  Timo Hautala 22,  Laure Farnault De Lassus 23,  Neal Rosen 3,  Omar Abdel-Wahab 24,  Benjamin H Durham 25
Affiliations

Affiliations

  • 1 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique-Hôpitaux de Paris (AP-HP), Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, 92100 Boulogne, France.
  • 3 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Sorbonne University, Assistance Publique-Hôpitaux de Paris, Pitié-Salpȇtrière Hospital, Internal Medicine Department 2, French Reference Centre for Histiocytosis, CIMI INSERM-UMRS 1135, 75013 Paris, France.
  • 5 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 9 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 10 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 11 Department of Molecular Imaging and Therapy, Hoag Family Cancer Institute, Irvine, CA, USA; Radiology and Translational Genomics, University of Southern California, Los Angeles, CA 90033, USA.
  • 12 Department of Hematology and Oncology, University Hospital, 8091 Zurich, Switzerland.
  • 13 Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; Translational Research Lab, Assuta Medical Centers, Tel-Aviv 52456, Israel.
  • 14 Adelson School of Medicine, Ariel University, Ariel 40700, Israel; Institute of Hematology, Assuta Medical Centers, Tel-Aviv 52456, Israel.
  • 15 Institute of Hematology, Assuta Medical Centers, Tel-Aviv 52456, Israel.
  • 16 Division of Hematology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
  • 17 Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 18 Service de Médecine Interne et Immunologie Clinique, Hôpital Claude Huriez, 59037 Lille, France.
  • 19 Department of Hematology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
  • 20 Département de Médecine Interne, CHU Timone, AP-HM, Aix-Marseille Université, 13007 Marseille, France.
  • 21 Servicio de Endocrinología Sanatorio Allende, Córdoba X5000, Argentina.
  • 22 Research Unit of Internal Medicine and Biomedicine, University of Oulu, 90570 Oulu, Finland.
  • 23 Service d'Hématologie, Hopital de la Conception, AP-HM, 13385 Marseille, France.
  • 24 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: abdelwao@mskcc.org.
  • 25 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Departments of Pediatrics and Pathology and Laboratory Medicine, Rutgers Cancer Institute, New Brunswick, NJ 08901, USA. Electronic address: bd559@cinj.rutgers.edu.
PMID: 41135521 DOI: 10.1016/j.ccell.2025.09.014
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; ERK; Erdheim-Chester disease; Langerhans cell histiocytosis; MEK; cobimetinib; histiocytoses; macrophage; trametinib; ulixertinib.

Figures
Products
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    Product Name
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  • HY-10528
    99.94%, S100A9 Inhibitor