Abstract 1664: Combination of LUNA18, a novel RAS inhibitor, with KRAS G12C inhibitors augments anti-tumor activity via inhibition of MAPK pathway reactivation

Abstract RAS gene alterations, found in approximately 15% of all cancers and known oncogenes, are recognized as promising therapeutic targets. KRAS G12C inhibitors were the first FDA-approved RAS targeting agent, but their efficacy of monotherapy is limited. Reactivation of the MAPK pathway is reported to be the one of the causes for attenuating efficacy of KRAS G12C inhibitors. LUNA18 is the cyclic peptide that binds to RAS mutants and wildtype, including KRAS, NRAS and HRAS, thereby inhibiting protein-protein interaction (PPI) between the inactive form of RAS and GEFs (guanine nucleotide exchange factors). We observed the rebound of ERK activation 24-72 hours after the treatment with a KRAS G12C inhibitor in cells with the KRAS G12C mutation though suppression of KRAS activity was maintained. This rebound was not suppressed by the KRAS G12C inhibitor retreatment. On the other hand, LUNA18 persistently suppressed ERK activity as well as KRAS activity up to 72 hours. LUNA18 also suppressed ERK reactivation caused by long-term treatment with the KRAS G12C inhibitor. The combination of the KRAS G12C inhibitor with siRNA for RAS wildtype showed durable inhibition of ERK activity, suggesting that RAS wildtype plays a key role for the rebound of ERK activity and inhibitory activity to RAS wildtype by LUNA18 contribute to the persistent inhibition of RAS signaling by LUNA18. In the experiment model that with strong RAS wildtype activation by stimulation with GFs (growth factors), the KRAS G12C inhibitor also did not suppress ERK activation. Conversely, LUNA18 suppressed it. Cell proliferation induced by GF stimulation was more strongly inhibited by LUNA18 than by the KRAS G12C inhibitors. Our data indicates that MAPK pathway reactivation via WT-RAS activation leads to resistance to KRAS G12C inhibitors and that the combination of LUNA18 and KRAS G12C inhibitors has the potential to overcome this resistance mechanism. In the in vitro cell growth assay, combination of LUNA18 and the KRAS G12C inhibitor showed more potent cell growth inhibition than single agents. We orally administered LUNA18 and the KRAS G12C inhibitor to a xenograft model, which showed temporal response and then acquired resistance to the KRAS G12C inhibitor, and found that LUNA18 significantly suppressed emergence of resistance to the KRAS G12C inhibitor. These results suggest that LUNA18 could be a promising candidate for combination therapy with KRAS G12C inhibitors. Citation Format: Saki Michisaka, Hitoshi Sase, Yukako Tachibana, Masami Hasegawa, Toshihiko Fujii, Shino Kuramoto, Norihito Shibahara, Atsushi Ohta, Mikihisa Tanada, Takuya Shiraishi, Hitoshi Iikura, Takehisa Kitazawa, Hiroshi Tanaka. Combination of LUNA18, a novel RAS inhibitor, with KRAS G12C inhibitors augments anti-tumor activity via inhibition of MAPK pathway reactivation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1664.