Daraxonrasib (RMC-6236) is an effective targeted therapy for RAS -mutant neuroblastoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Neuroblastoma (NB) is a common childhood extracranial solid tumor with poor outcomes in relapsed/refractory high-risk (HR) cases.
• Activating RAS-MAPK pathway mutations are frequent in HRNB, but existing targeted therapies have shown limited efficacy.
• Daraxonrasib (RMC-6236), a RAS(ON) inhibitor, has shown activity in adult cancers with RAS mutations.

Purpose of the Study:

• To evaluate the therapeutic efficacy of Daraxonrasib (RMC-6236) in neuroblastoma models with RAS pathway activation.
• To investigate the modulation of oncogenic signaling by RMC-6236 in these models.

Main Methods:

• Preclinical evaluation of RMC-6236 in neuroblastoma cell lines and mouse models harboring RAS or NF1 mutations.
• Assessment of cell viability, MAPK signaling suppression, BIM and BCL-2 expression, and BIM:BCL-2 complex formation.
• Combination therapy studies with the BCL-2 inhibitor venetoclax.

Main Results:

• RMC-6236 significantly decreased cell viability, suppressed MAPK signaling, and increased cell death in RAS-mutant and NF1-mutant NB models.
• In vivo studies demonstrated RMC-6236's on-target activity, reducing tumor growth and extending survival in RAS-mutant HRNB mouse models.
• RMC-6236 induced BIM and BCL-2 upregulation, and venetoclax enhanced RMC-6236-mediated cell killing by disrupting BIM:BCL-2 complexes.

Conclusions:

• Daraxonrasib (RMC-6236) is a rational targeted therapy for RAS-mutant neuroblastoma, a subset associated with poor outcomes.
• RMC-6236 effectively targets the MAPK pathway in neuroblastoma and warrants expanded clinical investigation.
• Combination therapy with venetoclax may further enhance treatment efficacy in RMC-6236-treated neuroblastoma.