Abstract 5948: FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistance
Authors: Yan Wang, Richard M. Neve, Jocelyn Staunton, Kevin R. Webster
Journal: Cancer Research (2024)

Abstract KRASG12C is a frequent activating mutation occurring in NSCLC, CRC, PDAC and other tumors that shifts KRAS into the active, GTP-bound (ON) state. KRAS was long considered undruggable until the recent discovery of single acting inhibitors, including those that bind the GDP-bound, inactive (OFF), state of KRASG12C. The most clinically advanced of these first-generation molecules have demonstrated clinical response rates of 37-43% and 6 to 7-month progression-free survival in lung cancer patients. While an important advance, a majority of cancers do not respond, and acquired resistance is common. FMC-376 is a next-generation dual inhibitor of both the ON and OFF states of KRASG12C with the potential to overcome resistance and deliver best-in-class durability of response. FMC-376 was discovered through the application of the FrontierTM platform, which integrates chemoproteomics, machine-learning, and covalent fragment-based drug discovery. FMC-376 is a highly selective, irreversible inhibitor of KRASG12C that covalently binds to the mutant cysteine in KRASG12C and directly blocks the ON and OFF states of the mutant KRAS protein leading to a complete, durable blockade of downstream signaling. This further translates into more durable tumor regressions in vivo in comparison to OFF state inhibitors like sotorasib. Clinical resistance to first-generation inhibitors that can only bind the OFF state of KRASG12C has been associated with multiple mechanisms that drive upregulation of ON state KRASG12C. These known drivers of resistance include activating co-mutation/amplification/fusions of receptor tyrosine kinases, amplification of KRASG12C and non-mutational mechanisms that lead to paradoxical activation of KRASG12C due to release of negative feedback control upon KRAS inhibition, often referred to as adaptive resistance. In addition, multiple mutations that may act independently of KRAS are also associated with resistance. These include mutation of KEAP1, CDKN2A, SMARCA4, PI3K, PTEN, MTOR, HRAS, NRAS, RAF, and MAPK. In vivo profiling of FMC-376 against a panel KRASG12C mutant patient derived xenograft (PDX) models of NSCLC, CRC and PDAC, has demonstrated that dual inhibition of both ON and OFF KRASG12C leads to complete suppression and regression of tumors carrying a broad spectrum of known genomic and non-genomic (adaptive) drivers of clinical resistance to OFF state KRASG12C inhibitors. FMC-376 a clinical stage dual inhibitor of ON and OFF state KRASG12C has the potential to overcome limitations of single acting and OFF state KRASG12C inhibitors. Citation Format: Yan Wang, Richard M. Neve, Jocelyn Staunton, Kevin R. Webster. FMC-376 a dual inhibitor of ON and OFF states of KRASG12C is broadly active in PDX models of resistance [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 5948.