Daraxonrasib (RMC-6236) is an effective targeted therapy for RAS -mutant neuroblastoma.
The preprint reports that daraxonrasib suppresses MAPK signaling, reduces viability and tumor growth, and extends survival in preclinical RAS-mutant neuroblastoma models, with venetoclax further enhancing cell killing through disruption of BIM:BCL-2 complexes.
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The preprint reports that daraxonrasib suppresses MAPK signaling, reduces viability and tumor growth, and extends survival in preclinical RAS-mutant neuroblastoma models, with venetoclax further enhancing cell killing through disruption of BIM:BCL-2 complexes.
Research significance
The supplied evidence supports preclinical sensitivity of RAS- and NF1-mutant neuroblastoma models to daraxonrasib; it further suggests—but does not clinically establish—that combining daraxonrasib with venetoclax could overcome BCL-2-mediated buffering of BIM and improve activity in selected relapsed or refractory neuroblastoma.
Source abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Relapsed or refractory (R/R) high-risk (HR) NB tumors continue to exhibit poor outcomes despite intensive and protractive multimodal therapy. Activating mutations in the RAS- mitogen-activated protein kinase (MAPK) pathway are frequently observed in R/R HRNB. The early promise of ALK inhibitors to treat ALK -mutant NB underscores the ability of appropriate targeted therapies to improve outcomes for HRNB patients. While MAPK pathway activation is prominent in HRNB, FDA-approved MEK inhibitors and KRAS G12C inhibitors have failed to demonstrate significant preclinical single-agent activity. Daraxonrasib (RMC-6236), a potent and selective RAS(ON) inhibitor, has demonstrated activity in both preclinical models and early phase clinical trials of RAS -mutant adult cancers. A subset of R/R HRNB tumors is noteworthy for containing diverse RAS- mutations, providing rationale for RMC-6236 investigation. In this study, we evaluated the therapeutic efficacy and oncogenic signaling modulation of RMC-6236 across NB models harboring RAS pathway activation. RMC-6236 as a single-agent treatment led to a significant decrease in cell viability, suppression of downstream MAPK signaling, upregulation of the MAPK pathway effector protein BIM, and increased cell death in RAS -mutant NB models as well as in NF1 -mutant NB models. In vivo studies evidenced that RMC-6236 had on-target activity that significantly reduced tumor growth and extended survival in RAS -mutant HRNB mouse models. Furthermore, RMC-6236-induced both BCL-2 and BIM upregulation and enhancement of BIM:BCL-2 complexes in RAS -mutant NB. As such, the BCL-2 inhibitor venetoclax further enhanced RMC-6236-mediated killing by disrupting RMC-6236 enhanced BIM:BCL-2 complexes. These findings demonstrate that RMC-6236 is a rationale targeted therapy for RAS -mutant NB, a subset of NB that is progressively understood as conferring particularly poor outcomes. RMC-6236 is a clinically relevant drug that can successfully target the MAPK pathway in these cancers. This study supports expanded clinical testing of this novel therapy to this important subset of neuroblastoma.