斯隆凯特琳学院Benjamin H. Durham研究小组揭示了不依赖RAF的MEK突变驱动难治性组织细胞肿瘤，但对ERK抑制有反应。相关论文于2025年10月23日发表在《癌细胞》杂志上。

通过对组织细胞病患者（NCT03329274）的前瞻性登记，该课题组人员发现，与其他MEK1/2突变类型的患者相比，MEK1/2抑制患者的无进展生存期较差，MEK1/2突变独立于RAF激活MEK。最常见的与RAF无关的MEK1突变（MEK1E102_I103del）在小鼠中驱动致死性组织细胞样肿瘤，该肿瘤对ERK1/2抑制剂乌利西替尼敏感。随后，课题组按照前瞻性方案用乌利西替尼治疗了5例MEK1E102_I103del突变患者，其中5例MEK抑制难治。5例患者中有4例对乌利西替尼有客观反应。这些数据揭示了体内致癌MEK突变的影响，确定了MEK抑制可能耐药的患者，并在组织细胞病中提出了ERK抑制克服MEK抑制耐药的方法。

据了解，组织细胞肿瘤是单核细胞/巨噬细胞谱系的克隆性疾病，由激活丝裂原活化蛋白激酶（MAPK）信号的突变定义。最近，MEK1/2抑制剂cobimetinib被FDA批准用于成人组织细胞增多症患者。

附：英文原文

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

Author: 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 Rsler, 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

Issue&Volume: 2025-10-23

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.

DOI: 10.1016/j.ccell.2025.09.014

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00406-4