Abstract 1654: Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors
Authors: Sase Hitoshi , Michisaka Saki , Tachibana Yukako , Hasegawa Masami , Fujii Toshihiko , Takei Kana , Kanei Tomoko , Murao Naoaki , Kuramoto Shino , Shibahara Norihito , Ohta Atsushi , Tanada Mikimasa , Shiraishi Takuya , Iikura Hitoshi , Kitazawa Takehisa , Tanaka Hiroshi 
Published: March 2024

Abstract
RAS is the one of the most frequently altered genes in human cancer and contributes to the growth of tumors. Recently, KRAS G12C inhibitors were approved as the first molecular targeting agents for RAS, but there are still huge unmet medical needs in RAS-mutated cancers because drugs targeting non-KRAS G12C tumors have not yet been approved and efficacy by even approved KRAS G12C inhibitors is not satisfactory. 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). LUNA18 decreased the active form of KRAS and phosphorylated ERK and AKT, and cell proliferation in RAS-mutated cancer cells with nM order of cellular IC50s irrespective of tumor types and amino acid substitutions except for Q61 mutants. On the other hand, LUNA18 did not inhibit proliferation of cells with active mutations downstream of RAS (BRAF and MEK), suggesting LUNA18 selectively inhibited growth of RAS-dependent cells. Consistent with in vitro cellular activity, oral administration of LUNA18 showed durable RAS signal inhibition up to 24-48 hours and tumor regression in RAS-mutated xenograft models. In addition to KRAS-mutated cells, LUNA18 also showed in vitro and in vivo robust efficacy in KRAS-amplified cells. These data indicated LUNA18 is the versatile compound that selectively suppressed cellular signaling from RAS G12/G13 mutants as well as RAS wildtype amplification through inhibition of PPI between the inactive form of RAS and GEFs, and it can be applicable to a wide range of RAS-altered tumors. Rebound of the MAPK pathway is reported to be the one of the cause for attenuating efficacy of KRAS G12C inhibitors. We also 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. On the other hand, LUNA18 persistently suppressed ERK activity as well as KRAS activity up to 72 hours. 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. We orally administered LUNA18 and a KRAS G12C inhibitor to a xenograft model, which showed temporal response and then acquired resistance to a KRAS G12C inhibitor, and found that LUNA18 significantly suppressed emergence of resistance to a KRAS G12C inhibitor. These results supported that the combination of the KRAS G12C inhibitor with LUNA18 could be a promising option to patients with KRAS G12C mutation by suppressing resistance to a KRAS G12C inhibitor through the suppression of rebound of the MAPK pathway.
Citation Format: Hitoshi Sase, Saki Michisaka, Yukako Tachibana, Masami Hasegawa, Toshihiko Fujii, Kana Takei, Tomoko Kanei, Naoaki Murao, Shino Kuramoto, Norihito Shibahara, Atsushi Ohta, Mikimasa Tanada, Takuya Shiraishi, Hitoshi Iikura, Takehisa Kitazawa, Hiroshi Tanaka. Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors [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(6_Suppl):Abstract nr 1654.