Abstract 1261: A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition

Abstract

The KRASG12C mutation is found in 11% of non-small cell lung cancers and 4% of colorectal cancers. Recently, a class of KRASG12C(OFF) inhibitors has shown promising activity in patients whose cancers bear KRASG12C. These data validate KRASG12C as an oncogenic driver, as well the mechanism of action of the KRASG12C(OFF) inhibitor class – sequestration of inactive, GDP-bound KRASG12C(OFF) proteins. Previous work has demonstrated this mechanism of action is vulnerable to adaptive tumor cell responses that activate KRASG12C by increasing upstream signaling and driving the cellular pool of KRASG12C towards the RAS(ON) state. These escape mechanisms, in which KRASG12C can be reactivated in the presence of a KRASG12C(OFF) inhibitor, highlight the potential for an inhibitor that directly targets and disables the KRASG12C(ON) form. Using structure-based drug design, we have discovered RM-032, a potent covalent inhibitor of KRASG12C(ON) that forms a tri-complex between KRASG12C(ON) and cyclophilin A (CypA), a highly abundant immunophilin. The assembled tri-complex prevents KRASG12C(ON) from signaling via steric blockade of RAS effector binding. In cells, kinetic analyses demonstrate near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. RM-032 is dual selective for KRASG12C(ON) and NRASG12C(ON). In vitro, RM-032 drives increased durability of inhibition of both RAS pathway signaling and cell proliferation in KRASG12C tumor cells compared with KRASG12C(OFF) inhibition. RM-032 displays attractive drug-like properties including cross-species oral bioavailability, and is predicted to achieve adequate exposures following oral dosing in humans. Oral administration of RM-032 produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo at well-tolerated doses. Across multiple tumor xenograft models, advanced KRASG12C(ON) inhibitors, including RM-032, appear to outperform KRASG12C(OFF) inhibitors. RM-032 permits a broad array of combination opportunities for treating KRASG12C mutant cancer types where single agent KRASG12C(ON) inhibition may be insufficient, for example with agents targeting nodes both upstream (e.g., SHP2 and SOS1) and downstream (e.g., MEK and ERK) of RAS, as well as parallel pathways (e.g., mTORC1). RM-032 is a next generation mutant-selective inhibitor of KRASG12C(ON) that may overcome liabilities of first-generation KRASG12C(OFF) inhibitors and provide additional benefit to patients by directly targeting the active form of this important oncogenic driver mutation. Citation Format: Robert J. Nichols, Jim Cregg, Christopher J. Schulze, Zhican Wang, Kevin Yang, Jingjing Jiang, Daniel M. Whalen, Rich Hansen, Lindsay S. Garrenton, Alun Bermingham, John E. Knox, Tiffany Choy, Denise Reyes, Mayra Rios, Kyle Seamon, Michael Longhi, Kang-Jye Chou, Shaoling Li, David P. Wildes, Mallika Singh, Elena S. Koltun, Adrian L. Gill, Jacqueline A. M. Smith. A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1261.

Targeting KRAS in Non-Small Cell Lung Cancer

“…The covalent tri-complex inhibitor of KRAS G12C (ON) exhibit a preclinical profile that is superior to the leading KRAS G12C (OFF) inhibitors in clinical development ( 13 , 56 ). RMC-6291 is a first-in-class, potent, oral and selective tri-complex inhibitor of KRAS G12C (ON) and NRAS G12C (ON) that has demonstrated deep and sustained anti-tumor activity in preclinical lung and colorectal cancer models driven by a KRAS G12C mutation ( 57 ), and RMC-6236, another first-in-class, potent, oral RAS-selective tri-complex RAS MULTI (ON) inhibitor, which has demonstrated pronounced anti-tumor activity in preclinical models of human lung, colorectal and pancreatic cancers caused by multiple RAS variants including KRAS G12D and KRAS G12V and also in RAS-dependent wt tumors and RAS-mediated adaptive resistance tumors ( 13 ). Both drugs are pending of being tested in early phase trials.…”

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

“… 64 Finally, targeting KRAS G12C in its GTP-bound state with inhibitors such as RM-032 would bypass mechanisms of resistance such as overexpression of active GTP-bound KRAS G12C protein, which are not targetable with the current agents. 65 …”

How to manage KRAS G12C-mutated advanced non-small-cell lung cancer

“…Interestingly, another recent approach to target KRAS mutations, including the KRAS G12C variant recently disclosed by Revolution Medicine, relies on the so-called ‘molecular glue’ mechanism targeting the active GTP state of KRAS and involving the formation of a tri-complex with cyclophilin. 28 Due to their ability to target GTP-bound KRAS (G12C), these compounds are referred as to RAS (ON) inhibitors. Amongst these, RMC-6291 shows sustained pathway inhibition following RTK activation, consistent with targeting the active form of KRAS G12C.…”

“… 52 , 53 In addition to irreversible covalent inhibitors, a new class of tri-complex inhibitors of the active GTP-bound (ON) form of KRAS G12 or RAS (ON) inhibitors are in preclinical development. RMC-6291 is a first-in-class, orally available, potent and selective tri-complex RAS (ON) inhibitor, which showed sustained pathway and cell growth inhibition in NSCLC cells in vitro , 28 and is currently being evaluated in early phase clinical trials in patients with KRAS G12C-mutated tumours (NCT05462717). Additionally, pharmaceutical companies are developing pan-KRAS inhibitors that inhibit SRC homology region 2–containing protein tyrosine phosphatase 2 (SHP2) or Son of sevenless homolog 1 (SOS1), preventing KRAS nucleotide exchange and activation.…”