MRTX1133 is a potent non-covalent KRAS (G12C) inhibitor with tissue-specific activity

Abstract

KRAS is a high-value therapeutic target for the treatment of cancer. Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), have received accelerated approvals for clinical use. Studies of these inhibitors ushered in the development of new inhibitors such as MRTX1133, that had entered clinical trials as a KRAS (G12D)-selective, non-covalent inhibitor. However, the subsequent failure of sotorasib as monotherapy and the recent termination of an early-phase clinical trial for MRTX1133 indicates that developing clinically effective allele-specific KRAS inhibitors remains a challenge, and that there is a need for further evaluation of KRAS inhibition mechanisms. Here, we show that the reportedly KRAS (G12D)-selective MRTX1133 also binds to G12C mutant KRAS with high affinity and suppresses MAPK signaling in cancer cell lines harboring KRAS (G12C). Intriguingly, its effect on the proliferation of KRAS (G12C) cancer cells is context-dependent; MRTX1133 robustly inhibits the proliferation of the pancreatic cancer cell line MIA PaCa-2 as well as the tumor growth of MIA PaCa-2 mouse xenografts, but it has little effect in lung cancer cells. These findings, together with similar other recent reports, question if allele-specific KRAS inhibitors are truly selective and highlight the need for strategies that take into account tissue and context-specific processes. Significance StatementMRTX1133 is a reportedly selective, non-covalent inhibitor for the KRAS oncogene with a glycine-to-aspartate (G12D) mutation that is present in about 40% of pancreatic cancers. Despite the overwhelming preclinical success, the early-phase clinical trial of MRTX1133 was recently terminated with undisclosed results. Through our in vitro and in vivo studies, we discovered that MRTX1133 is also a potent non-covalent inhibitor of a glycine-to-cysteine (G12C) KRAS mutation that works in pancreatic cancer but not in lung cancer models. Our findings are consistent with other recent reports on the activity of MRTX1133 in non-G12D mutants and highlight challenges in developing true allele-specific KRAS inhibitors via non-covalent mechanisms while also accounting for tissue-specific effects.