Abstract A144: HM99462, a Novel & potent SOS1 inhibitor, induces tumor regressions in combination with KRAS G12C inhibitor, MEK inhibitor, or EGFR mutant inhibitor

Abstract

Abstract Son of sevenless homolog 1 (SOS1) is one of guanine nucleotide exchange factor (GEF) responsible for a binary molecular switch to activate KRAS as well as a node in the negative feedback loop in the RTK-KRAS-MAPK signaling pathway. Therefore, combination strategies with a SOS1 inhibitor are being explored as a promising therapeutic options to target the MAPK-mediated bypass, which may improve antitumor activity or delay the induction of resistance after treatment. Herein, we presented a novel and potent SOS1 inhibitor, HM99462, which abrogates GTP-binding to KRAS and the profile of drug potency and mechanism of action was examined with in vitro and in vivo models. Biochemical activity on SOS1 was evaluated by a GTP-exchange assay on diverse KRAS G12X mutant types, NRAS Q61H, and HRAS G12V, and HM99462 showed excellent inhibitory activity, while SOS2 action was not affected. Moreover, HM99462 decreased ERK phosphorylation in various cancer cell lines harboring different major KRAS mutation statuses such as KRAS G12C, G12D, G12V, or G13D. Growth inhibition assay was performed using a three-dimensional (3D) conformation culture that mimics the complexity and heterogeneity of tumors and has elevated p-ERK. In this 3D spheroid growth inhibition assay, HM99462 demonstrated significantly effective GI50 against various KRAS mutant cancer cell lines. Additionally, HM99462 was evaluated in cancer cell xenograft mouse models harboring KRAS or EGFR mutation. The combination of HM99462 with KRAS G12C, MEK, or EGFR mutant inhibitor led to significantly synergistic anti-tumor activity in both in vitro and in vivo models with several KRAS or EGFR mutations. Based on our exploratory study, a novel and potent SOS1 inhibitor, HM99462 could be suggested as an appropriate therapeutic agent for diverse inhibitory activity against cancers causing by the hyperactivation of oncogenic KRAS or RTK signaling. And it has the potential to overcome the limitations of KRAS G12C, MEK or EGFR inhibitor through combination. IND enabling GLP-toxicity studies with HM99462 are currently underway, and we planned to initiate clinical study in early 2024. Citation Format: Jaeyul Choi, Seung Hyun Jung, Wongi Park, Jooyun Byun, Semi Lim, Youngjoo Lee, Soye Jeon, Yu-Yon Kim, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. HM99462, a Novel & potent SOS1 inhibitor, induces tumor regressions in combination with KRAS G12C inhibitor, MEK inhibitor, or EGFR mutant inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A144.