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Constitutively activating MEK1 mutations drive treatment refractory histiocytic neoplasms but confer response to ERK inhibition

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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Project description:The pathophysiology of neurodegenerative diseases is poorly understood, and therapeutic options are few. Neurodegenerative diseases are hallmarked by progressive neuronal dysfunction and loss, associated with chronic glial and immune activation1. Microglia are the resident macrophages of the nervous system thought to be important for the clearance of debris after neuronal damage and aid to repair and regeneration. Their activation is viewed in general as a reactive process in neurodegeneration1-3. Whether microglia itself may be causative of neurodegenerative diseases is unclear. Late-onset neurodegenerative disease is frequently observed in patients with histiocytoses4-10, which are clonal myeloid diseases associated with somatic mutations in the RAS/MEK/ERK pathway such as BRAFV600E 5,11,12, suggesting a possible role of somatic mutations in neurodegeneration. Yet, expression of BRAFV600E in the hematopoietic stem cell (HSC) lineage does not cause neurodegeneration13,14. However, recent works from our laboratories and other have revealed that microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk sac erythro-myeloid progenitors (EMP) distinct from HSC15-18. We thus hypothesized that somatic BRAFV600E mutations in the resident macrophage lineage may cause neurodegeneration. We found that while BRAFV600E expression in the HSC lineage causes leukemic and tumoral diseases13,14, its expression in the EMP lineage instead results in a severe late-onset neurodegenerative disorder. Neurological symptoms, neuronal death, astrogliosis, immune activation, and amyloid precursor protein deposition were driven by ERK-activated microglia clones and preventable by RAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses, and demonstrate that a somatic mutation in the EMP lineage can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegenerative disease, and provide opportunities for therapeutic intervention aimed at preventing neuronal death in neurodegenerative diseases

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Constitutively activating MEK1 mutations drive treatment refractory histiocytic neoplasms but confer response to ERK inhibition

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