Constitutively activating MEK1 mutations drive treatment refractory histiocytic neoplasms but confer response to ERK inhibition
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ABSTRACT: Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of patients, which confer robust responses to BRAF inhibition. More recently, the MEK inhibitor cobimetinib was FDA-approved for BRAFV600-wild-type histiocytosis patients. Here following genomic analysis of 500 pediatric and adult patients with diverse histiocytoses, the most common alteration following BRAFV600E was MEK1E102_I103 in-frame deletion. MEK1E102_I103del and related RAF-independent MEK mutants were associated with an aggressive multi-system clinical phenotype with worse progression-free survival with MEK inhibition as compared to patients with other classes of MEK1/2 mutations. Given that cancer-associated MEK1/2 mutations have not been modeled in vivo and the clinical importance of MEK1 mutations in histiocytoses, we generated MEK1E102_I103del conditional knock-in mice. Using three distinct hematopoietic Cre drivers, these mice developed a 100% penetrant, lethal disorder by 6 weeks of age with expansion of classical and non-classical monocytes, macrophages, and Cd11b+ conventional dendritic cells which infiltrated hematopoietic organs, liver, and skin. MEK1-mutant mice were sensitive to single-agent treatment with the oral ERK inhibitor ulixertinib. We consequently treated five MEK1E102_I103del-mutant patients with ulixertinib on prospective IRB-approved Single Patient Use Expanded Access protocols, four of whom had disease refractory to MEK inhibition. Four of five patients experienced objective clinical and/or radiological responses to ulixertinib. These data reveal the impact of oncogenic MEK kinase mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition as a therapeutic approach to overcome resistance to MEK inhibition in histiocytoses.
ORGANISM(S): Mus musculus
PROVIDER: GSE268618 | GEO | 2024/09/03
REPOSITORIES: GEO
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