The most common variant of the small GTPase KRAS is KRASG12D, which occurs in 36% of human pancreatic ductal adenocarcinomas. KRAS mutation is a founding event in these lesions, among other cancer types. KRASG12D is difficult to target because it lacks a chemically reactive residue in the switch II binding pocket that is present in other KRAS variants and is crucial for the covalent binding of targeted agents. In previous work, these researchers identified the potent and highly selective KRASG12D inhibitor MRTX1133. Now, Hallin et al. have investigated the mechanism of action and anti-tumor efficacy of MRTX1133.
They showed that MRTX1133 exploits non-classical hydrogen bonding and ion-pair interactions within the binding pocket that lock KRASG12D in the inactive state and prevent the binding of effector proteins. In the majority of KRASG12D-mutant cancer cell lines tested, MRTX1133 potently and selectively inhibited KRASG12D-dependent pathways and induced apoptotic cell death. Moreover, MRTX1133 treatment caused tumor regression in 11 of 25 KRASG12D cancer xenograft models. This agent was well tolerated at intraperitoneal doses up to 30 mg per kg body weight and performed particularly well in pancreatic ductal adenocarcinoma xenografts, despite their desmoplastic stroma, which hinders the tissue distribution of small-molecule inhibitors: MRTX1133 induced tumor regression of 30% or more in 8 of 11 such models. Because some cancer cells are able to bypass the effects of KRASG12D inhibition, Hallin et al. conducted RNA sequencing and gene-deletion studies to identify collateral pathways that influence the response to KRASG12D inhibition and could be targeted by combination treatment. Combinations with inhibitors of the growth factor receptor HER (such as cetuximab and afatinib) or the kinase PI3Kα inhibitor BYL-719 synergistically increased the anti-tumor efficacy of MRTX1133. Notably, some of the combinations identified were specific to MRTX1133, whereas others were shared across KRAS inhibitors.
This is a preview of subscription content, access via your institution