The ERK MAPK pathway in mesenchymal glioblastoma: tumorigenesis, microenvironmental reprogramming, and the therapeutic promise of RAS(ON) multi-selective inhibition
TL;DR
The potential effect of daraxonrasib as an emerging targeted therapeutic candidate in MES-GBM is discussed, highlighting the need of further research and clinical evaluation to better determine its therapeutic efficacy dedicated GBM preclinical models.
Abstract
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.