Abstract 6782: Discovery of a new class of mutant-targeted catalytic RAS(ON) inhibitors with retained antitumor activity in setting of emergent resistance due to elevated RAS flux

Abstract RAS family proteins regulate cell growth by transitioning between GTP-bound (ON) and GDP-bound (OFF) conformations. Transition to the OFF state is facilitated by endogenous GTPase activating proteins (GAPs). Oncogenic mutations in RAS - among the most prevalent genetic events in human cancer - perturb this regulatory cycle by disrupting GAP-mediated stimulation of GTP hydrolysis, leading to sustained RAS activation. The investigational RAS(ON) multi-selective inhibitor daraxonrasib has a dual mechanism of RAS(ON) inhibition: disrupting RAS(ON) effector binding and activating RAS(ON) GTPase activity. Daraxonrasib has demonstrated encouraging response rates and durable antitumor activity with acceptable tolerability in patients with RAS-addicted cancers. Additional strategies are needed to counter emergent drug resistance and further extend clinical benefit. The majority of acquired genomic resistance mechanisms to daraxonrasib converge on reactivation of RAS(ON) and, in particular, RAS gene amplification, highlighting a potential opportunity for RAS(ON) inhibitors less sensitive to such resistance mechanisms. We have leveraged our understanding of tri-complex RAS(ON) inhibitors to design a new class of inhibitors that mimic the catalytic activity of natural GAPs. These compounds bind non-covalently to cyclophilin A to form a binary complex that selectively engages RAS(ON) proteins, including mutant and wild-type variants. The primary mechanism of action of these catalytic RAS(ON) inhibitors is to markedly accelerate the GTPase activity of oncogenic RAS mutants and promote conversion of RAS(ON) to RAS(OFF). Importantly, a single CYPA:catalytic RAS(ON) binary complex can inactivate multiple RAS(ON) proteins. In G12-mutant cell lines the catalytic RAS(ON) inhibitors more efficiently reduced RAS-GTP levels and exhibited more potent inhibition of RAS(ON) signaling and cell proliferation compared to daraxonrasib. In vivo oral administration of the catalytic RAS(ON) inhibitor RM-055 preferentially suppressed RAS pathway activation in G12-mutant tumors relative to normal tissues. At well-tolerated doses RM-055 demonstrated robust antitumor activity represented by deep and particularly durable responses across a panel of G12-mutant xenograft and syngeneic models of PDAC, NSCLC, and CRC, including models refractory to daraxonrasib monotherapy. Furthermore, RM-055 overcame acquired resistance to RAS(ON) inhibition, driving deep and durable regressions in models with elevated oncogenic RAS signaling, such as those with RAS amplification. Collectively, these preclinical data support evaluation of the potential of this new class of mutant-targeted catalytic RAS(ON) inhibitors to sustain clinical antitumor activity in the setting of emergent resistance mechanisms that rely on enhanced RAS pathway flux. Citation Format: Kyle Seamon, Jingwei Yin, Ouma Onguka, Oliver Lai, Cristina Blaj, Lingyan Jiang, Jinyu Liu, Yue Huang, Abby Marquez, John Knox, Jim Cregg, Yongxian Zhuang, Yu Chi Yang, Urszula N. Wasko, Qiang Liu, Jennifer A. Roth, Matthew G. Rees, Melissa Ronan, Benjamin J. Maldonato, Muhammad Ali Al-Radhawi, Kartika Jayashankar, Zhican Wang, Mike Flagella, Elsa Quintana, Elena S. Koltun, Mallika Singh, Zhengping Wang, Adrian L. Gill, David Wilds, Jingjing Jiang, Jacqueline A. Smith, Matthew Holderfield. Discovery of a new class of mutant-targeted catalytic RAS(ON) inhibitors with retained antitumor activity in setting of emergent resistance due to elevated RAS flux [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6782.