Innovative KRASG13C Inhibitor: Preclinical Evidence for Tumor Regression and Therapeutic Potential

The success of KRASG12C inhibitors in the clinic has highlighted the potential of targeting oncogenic RAS mutations with covalent drugs. However, KRASG12C inhibitors are ineffective against another cysteine mutation, KRASG13C, which is prevalent in non-small cell lung cancer (NSCLC). There is a gap in knowledge regarding the biochemical and cellular characteristics of KRASG13C, and no targeted therapies are currently available for KRASG13C-driven cancers.

This study introduces a potent and selective inhibitor, RM-041, designed to target KRASG13C. It is an orally bioavailable tri-complex inhibitor that forms a stable complex with KRASG13C and cyclophilin A (CypA), an intracellular protein. RM-041's mechanism involves a rapid steric blockade of RAS effector binding and a covalent modification that results in an irreversibly inhibited KRASG13C complex.

In cellular studies, RM-041 effectively suppresses RAS pathway signaling and inhibits the proliferation of cancer cells harboring the KRASG13C mutation. In xenograft tumor models, RM-041 given orally leads to significant and sustained suppression of RAS activity and tumor regression at doses that are well-tolerated.

KRASG13C is distinguished by a higher intrinsic nucleotide exchange rate, which diminishes its reliance on guanine nucleotide exchange factors (GEFs) and increases its resistance to upstream inhibitors. This underscores the necessity for direct targeting of KRASG13C. Additionally, KRASG13C shows unique sensitivity to specific GTPase-activating proteins (GAPs), including neurofibromin 1 (NF1). Analysis of patient tumor samples indicates a high occurrence of NF1 loss-of-function (LOF) mutations, which likely amplify wild-type RAS signaling.

The preclinical findings support a therapeutic strategy that combines mutant-selective KRASG13C inhibition with RM-041 and simultaneous targeting of an upstream regulator, such as SHP2, to manage cooperative wild-type RAS signaling. RM-041 represents a first-in-class, mutant-selective, oral inhibitor of KRASG13C with the potential to fill an unmet need for patients with KRASG13C mutant cancers, warranting its progression towards clinical assessment.