Abstract 6944: Transient pan-RAF inhibitor treatment for melanoma prevention

Abstract Therapeutic options are currently limited for the 15-25% of cutaneous melanomas driven by an oncogenic NRAS mutation. Our previous findings showed that melanoma-associated NRAS substitutions stabilize conformations optimal for BRAF binding, thereby promoting RAF dimerization, proliferative signaling, and ultimately melanomagenesis. Building on these discoveries, we hypothesized that NRAS-mutant melanoma precursors would exhibit substitution-specific sensitivity to pan-RAF inhibition, and that a temporary blockade of RAF signaling would eliminate NRAS mutant-melanocytes in the skin. BRET and NanoBiT complementation assays revealed that pan-RAF inhibitors promote RAS-RAF and RAF-RAF interactions at lower doses in human melanoma cell lines with a weakly melanomagenic NRAS substitution (Q61H) compared to those with a stronger melanomagenic NRAS substitution (Q61R). Surprisingly, these drug-induced RAF complexes were associated with decreased MAPK>ERK signaling and higher drug sensitivity, suggesting that fully inhibited, drug-bound protomers drive increases in NRAS-RAF interactions. To test the mutation-specific sensitivity of NRAS-mutant melanoma precursors in vivo, mouse models of spontaneous NRAS Q61R- or Q61H-driven melanoma were prophylactically treated with a pan-RAF inhibitor for three days and then followed for tumor formation. Consistent with our in vitro data, short-term pan-RAF inhibitor treatment delayed melanoma onset in NRAS Q61H, but not Q61R mice. These findings highlight the critical role of RAF signaling in NRAS-mutant melanoma formation, suggesting that short-term use of effective, targeted therapies could prevent melanoma formation. Citation Format: Rachel E. Lew, Harsha S. Sanaka, Venkat R. Chirasani, Sharon L. Campbell, Christin E. Burd. Transient pan-RAF inhibitor treatment for melanoma prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6944.