RAF-independent <i>MEK1</i> -mutant Histiocytoses Respond to ERK Inhibition

Mutations in mitogen-activated protein kinase (MAPK) signaling pathways are frequently found in histiocytic neoplasms, which comprise rare clonal disorders that can lead to aggressive tumorous lesions. The FDA-approved BRAF inhibitor vemurafenib has demonstrated strong efficacy in patients with BRAFV600E-mutant histiocytoses, with minimal cases of resistance. However, in patients with ERK-activating mutations with wild-type BRAF, inhibition of MEK1/2 showed less favorable outcomes. Patients who progress on BRAF and MEK inhibitors lack alternative treatment options. Thus, Diamond, Emile, Fujino, and colleagues utilized a large patient dataset and identified the MEK1E102_I103del mutation as a frequent and targetable alteration in histiocytoses. Analysis of genomic and clinical data from 498 patients with histiocytoses revealed that MEK1/2 mutations were the second most frequent alteration following BRAF, with the RAF-independent class 3 MEK1E102_I103del mutation being the most prevalent within this group. Notably, patients with class 3 MEK mutations had reduced progression-free survival and more frequently progressed with MEK1/2 inhibition compared to class 1 or 2. MEK1E102_I103del conditional knock-in mice displayed myelomonocytic neoplasms reminiscent of human histiocytoses, including expansion of mature myeloid cells and granuloma formation in the bone marrow, spleen, and liver, with a corresponding increase in MEK1/2 and ERK1/2 phosphorylation. Single-cell RNA sequencing analysis of the bone marrow and spleen revealed higher numbers of mature monocytes and macrophages with a decrease in B, T, and NK cells in MEK1-mutant compared to wild-type mice. Further, MEK1-mutant monocytes from the spleen showed higher expression of inflammatory markers, including IL1β and TNFα. Transplantation of MEK1E102_I103/WT hematopoietic cells into recipient mice revealed similar phenotypes, indicating the cell autonomous nature of MEK1E102_I103del-driven histiocytosis. Because class 3 MEK mutations lead to ERK activation, the therapeutic potential of the ERK1/2 inhibitor ulixertinib was evaluated. MEK1-mutant mice treated with ulixertinib showed increased survival with decreased proliferation of monocytes, hepatosplenomegaly, and inflammatory cytokines. Further, four out of five patients who received ulixertinib demonstrated partial or complete responses. Collectively, these data highlight the promise in treating RAF-independent class 3 MEK1-mutant histiocytoses with ERK inhibition.Diamond EL, Emile J, Fujino T, Haroche J, Maron MI, Lewis AM, et al. RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition. Cancer Cell 2025 Oct 23 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.