Inhibition and degradation of NRAS with a pan-NRAS monobody.

Abstract

The RAS family GTPases are the most frequently mutated oncogene family in human cancers. Activating mutations in either of the three RAS isoforms (HRAS, KRAS, or NRAS) are found in nearly 20% of all human tumors with NRAS mutated in ~25% of melanomas. Despite remarkable advancements in therapies targeted against mutant KRAS, NRAS-specific pharmacologics are lacking. Thus, development of inhibitors of NRAS would address a critical unmet need to treating primary tumors harboring NRAS mutations as well as BRAF-mutant melanomas, which frequently develop resistance to clinically approved BRAF inhibitors through NRAS mutation. Building upon our previous studies with the monobody NS1 that recognizes HRAS and KRAS but not NRAS, here we report the development of a monobody that specifically binds to both GDP and GTP-bound states of NRAS and inhibits NRAS-mediated signaling in a mutation-agnostic manner. Further, this monobody can be formatted into a genetically encoded NRAS-specific degrader. Our study highlights the feasibility of developing NRAS selective inhibitors for therapeutic efforts.