The ERK MAPK pathway in mesenchymal glioblastoma: tumorigenesis, microenvironmental reprogramming, and the therapeutic promise of RAS(ON) multi-selective inhibition.

Glioblastoma (GBM) remains one of the most lethal malignancies in adults, with a median survival of 15 months under the current standard of care. The lack of effective targeted therapies is a critical gap, particularly for the mesenchymal subtype of glioblastoma (MES-GBM), which accounts for up to 49% of GBM cases and carries the worst prognosis. Although direct RAS mutations are rare in GBM, mutations in upstream ERK MAPK pathway regulators such as loss-of-function of neurofibromin 1 (NF1) and gain-of-function mutations in epidermal growth factor receptor (EGFR) are highly prevalent in MES-GBM and drive constitutive pathway hyperactivation, chemoresistance, and aggressive tumor behavior. These mutations render the ERK MAPK pathway a compelling, yet underexplored, therapeutic target in GBM. RAS(ON) multi-selective inhibitors, which act upstream by blocking active RAS-GTP across multiple isoforms and mutations, represent a new therapeutic opportunity. Daraxonrasib (RMC-6236), a potent RAS(ON) multi-selective inhibitor currently in Phase III clinical trials for pancreatic cancer, has demonstrated blood-brain barrier (BBB) penetrance in non-GBM brain metastasis models, broad efficacy across RAS-driven cancers, and a favorable tolerability profile in clinical studies. As daraxonrasib targets active RAS regardless of mutation status, it is mechanistically suited for NF1-mutant GBM, in which RAS itself is wild-type but constitutively activated. Beyond direct tumor cell effects, hyperactive RAS signaling in GBM drives pro-tumoral reprogramming of microglia and tumor-associated macrophages (TAMs), creating an immunosuppressive microenvironment that further promotes MES-GBM transition and treatment resistance. RAS(ON) inhibition therefore holds potential to simultaneously suppress tumor proliferation and remodel the tumor microenvironment (TME) toward an anti-tumor state. In this review, we discuss the potential effect of daraxonrasib as an emerging targeted therapeutic candidate in MES-GBM, highlighting the need of further research and clinical evaluation to better determine its therapeutic efficacy dedicated GBM preclinical models.