MRTX1133 is a high-affinity, selective, and potent KRASG12D inhibitor with antitumor efficacy.

  • Major Finding: MRTX1133 is a high-affinity, selective, and potent KRASG12D inhibitor with antitumor efficacy.

  • Concept: Cotargeting of MRTX1133 with EGFR or PI3Kα demonstrates synergy and enhanced antitumor activity.

  • Impact: These results support the use of this inhibitor in KRASG12D-mutant tumors to reduce growth and improve survival.

Despite being one of the most commonly mutated oncogenes, KRAS remains difficult to directly target. Progress has been made in the development of covalent small-molecule inhibitors targeting the KRASG12C mutation, but targeting KRASG12D, the most common KRAS mutation, has continued to be a challenge. Using a structure-based drug design strategy, Hallin and colleagues identified and characterized MRTX1133, a high-affinity, selective, and potent noncovalent inhibitor of KRASG12D. Biochemical assays indicated that MRTX113 binds to both the inactive GDP-bound and active GTP-bound forms of KRASG12D with a greater than 700-fold selectively for the mutant versus wild-type KRAS, and MRTX1133 binding induced a conformational change in the switch I and switch II loops, both critical for downstream effector activity. Moreover, assessment of downstream signaling and viability after drug treatment revealed a concentration-dependent inhibition of phosphorylated ERK1/2, S6, and 4EBP1 as well as reduced viability in multiple KRASG12D-mutant cell lines and xenograft tumor models of pancreatic and colorectal cancers. Moreover, MRTX1133 treatment led to tumor regression in a majority of human cell line–derived and patient-derived xenografts with KRASG12D mutations. RNA sequencing data obtained from tumor xenograft–bearing mice obtained either 6 hours or 24 hours after the last of three consecutive MRTX1133 doses indicated differentially expressed genes in KRAS signaling, MYC targets, MTORC1, E2F targets, and G2M checkpoint pathways, with additional CRISPR–Cas9 screens demonstrating that cotargeting EGFR, PI3Kα, or SHP2 could complement KRASG12D inhibition and augment MRTX1133 activity. Furthermore, evaluation of targeted therapies that can increase MRTX1133 response indicated that combination with MEK or ERK inhibitors did not enhance activity, but combination with SHP2, SOS1, mTOR, or CDK4/6 inhibitors led to a modest effect on cell viability. However, the greatest synergy was observed with afatinib and cetuximab, both HER family inhibitors, along with BYL-719, a PI3Kα inhibitor, with both cetuximab and BYL-719 enhancing the activity of MRTX1133 in in vivo models of colon and pancreatic cancer. In conclusion, this study characterizes, MRTX1133, a specific and potent inhibitor of KRASG12D, with the results suggesting therapeutic susceptibility of KRASG12D-mutant tumors to this small molecule.

Hallin J, Bowcut V, Calinisan A, Briere DM, Hargis L, Engstrom LD, et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat Med 2022;28:2171–82.

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