MRTX1133 suppresses ERK signaling but elicits context-dependent antiproliferative responses in KRAS (G12C) cancer cells.

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), had 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 indicate 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 KRAS (G12D)-selective MRTX1133 also binds to G12C mutant KRAS with high affinity and suppresses nucleotide exchange and MAPK signaling in cancer cell lines harboring KRAS (G12C). However, 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 minimal effect in lung and colorectal cancer cells. This appears to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.