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RAS(ON) Multiselective Inhibition Drives Antitumor Immunity in Preclinical Models of NRAS-Mutant Melanoma
Larissa Anastacio Da Costa Carvalho1, Nataliya Tovbis Shifrin2, Manali S Phadke1
1Department of Tumor Microenvironment and Metastasis, Moffitt Cancer Center, Tampa, Florida.
Abstract:
Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. In this study, we demonstrate that RMC-7977, a preclinical RAS(ON) multiselective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of MHC and PD-L1 proteins, and enhanced infiltration of CD4+ and CD8+ T cells. Complete responses were dependent on adaptive immunity, as both CD4+ and CD8+ T cells were essential for extended survival. Resistance to treatment was marked by reduced T-cell infiltration, loss of MHC class I expression, and expansion of myeloid-derived suppressor cells. Combining RMC-7977 with anti-PD-1 boosted cytotoxic T-cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Consistent with these preclinical data, objective clinical responses were observed in two patients with NRAS-mutant melanoma treated with daraxonrasib in an ongoing phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multiselective inhibitors for the treatment of NRAS-mutant melanoma.
Insights
A new targeted therapy, daraxonrasib, shows promise for NRAS-mutant melanoma by activating anti-tumor immunity. This RAS(ON) inhibitor promotes T-cell responses and tumor regression, offering a potential new treatment option.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- NRAS-mutant melanoma lacks effective targeted therapies.
- RAS(ON) signaling pathways are crucial in melanoma development.
Purpose of the Study:
- To evaluate the efficacy of RMC-7977, a preclinical RAS(ON) multiselective inhibitor (daraxonrasib), in NRAS-mutant melanoma models.
- To investigate the immune mechanisms underlying RMC-7977's antitumor activity.
- To assess combination therapy with anti-PD-1 and clinical responses.
Main Methods:
- In vivo studies using NRAS-mutant melanoma models.
- Assessment of MAPK signaling, immune cell infiltration (CD4+, CD8+ T cells), MHC and PD-L1 expression.
- Combination therapy with RMC-7977 and anti-PD-1.
- Analysis of clinical data from a Phase I/Ib trial.
Main Results:
- RMC-7977 induced rapid tumor regressions and potent antitumor immune responses.
- Treatment upregulated MHC and PD-L1, enhancing T-cell infiltration and activity.
- Resistance was associated with reduced T-cell infiltration and altered myeloid cell populations.
- Combination therapy overcame resistance and improved survival.
- Two patients with NRAS-mutant melanoma showed objective clinical responses.
Conclusions:
- RAS(ON) multiselective inhibition with daraxonrasib is a promising strategy for NRAS-mutant melanoma.
- The drug elicits antitumor immunity dependent on adaptive T-cell responses.
- Combination therapy may overcome resistance to PD-1 blockade.
- Further clinical evaluation of daraxonrasib is warranted.
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