Abstract A066: SOS1-panKRAS modulator, HM101207: A top candidate to control KRAS-MAPK-driven cancers through strong synergy with vertical inhibitors

Abstract KRAS, the most frequently mutated member of the RAS gene family, acts as a molecular switch between off (inactive) and on (active) states. KRAS-driven cancers, including non-small cell lung, colorectal, and pancreatic cancers, are challenging due to their high prevalence and poor outcomes. Although KRAS was once considered “undruggable,” the recent approval of KRAS G12C inhibitors has brought hope, particularly for NSCLC and CRC patients with the G12C mutation. However, the clinical benefit of KRAS G12C inhibitors remains limited, largely due to the emergence of resistance mechanisms including secondary KRAS mutations, KRAS wt amplification, RTK bypass signaling, and activation of upstream regulators such as SOS1. Particularly, the key mechanism is ERK pathway reactivation through the relief of negative feedback triggered by KRAS inhibition. SOS1 is a guanine nucleotide exchange factor that plays a pivotal role in converting KRAS from its GDP-bound (inactive) state to its GTP-bound (active) form. Beyond being a key activator of RAS, SOS1 itself is embedded in a complex network of feedback regulation. In the tumor environment, inhibition of the KRAS-MAPK pathway relieves ERK-dependent negative feedback on SOS1, enabling SOS1 to hyperactivate KRAS signaling, which ultimately promotes uncontrolled cell growth. In this aspect, targeting of SOS1 provides a promising therapeutic strategy to overcome the resistance of KRAS inhibitor and drive the durable anticancer effects. Herein, we present HM101207, a SOS1-panKRAS modulator with anti-tumor efficacy as a monotherapy and potent synergistic effects when combined with inhibitors targeting the KRAS-MAPK signaling pathway. HM101207 blocks protein-protein interaction between SOS1 and KRAS, preventing GTP binding to KRAS, and its mechanism of action was evaluated in both in vitro and in vivo models. HM101207 blocks SOS1-mediated GTP exchange in KRAS wild-type, G12C/D/S/V/R, Q61H mutants, and demonstrates promising potency by evaluating its inhibitory effect on ERK phosphorylation and 3D cell viability across a panel of tumor cell lines with KRAS-related mutations. Moreover, HM101207 exhibits superior selectivity, which is expected to offer significant benefits when used in combination therapy. Oral administration of HM101207 as monotherapy demonstrated meaningful tumor growth inhibition in preclinical models. Additionally, combining it with RTK, KRAS G12C and MAPK signaling inhibitors resulted in powerful synergistic anti-tumor effects in both in vitro and in vivo models of various KRAS-mutant cancers. Based on our exploratory studies, HM101207 emerges as an attractive therapeutic candidate with broad-spectrum efficacy against KRAS-mutated cancers. And it has the potential to overcome the limitations of KRAS-MAPK pathway inhibitors through combination. Currently, HM101207 is undergoing GLP toxicology studies for IND submission. Citation Format: Seung Hyun Jung, Jaeyul Choi, Wongi Park, Soye Jeon, Heesun Moon, Jooyun Byun, Young Gil Ahn. SOS1-panKRAS modulator, HM101207: A top candidate to control KRAS-MAPK-driven cancers through strong synergy with vertical inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A066.