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Research
KRAS Becomes Druggable
RAS is the most frequently mutated oncogene in human cancer and an obvious drug target, but efforts to directly inhibit mutant KRAS proteins had long been unsuccessful due to the absence of an obvious drug-binding site. A 2013 study showed that it was in fact possible to directly inhibit the GTPase activity of KRAS (specifically the KRASG12C mutant) with compounds that bound a previously uncharacterized allosteric pocket near the effector binding switch-II region. In 2016, Patricelli, Janes, Liu, and colleagues presented the first direct KRASG12C inhibitor with activity in human cancer cells and not only demonstrated that KRASG12C is a hyperexcitable protein that rapidly cycles bound nucleotide but that a covalent mutant-specific inhibitor stabilizes the GDP-bound inactive state. These findings provided a framework for further development of KRASG12C inhibitors, and in 2020, Hallin, Christensen, and colleagues reported the preclinical characterization and early clinical proof-of-concept for the KRASG12C inhibitor MRTX849. A potent, selective inhibitor of KRASG12C, MRTX849 blocked KRAS-dependent signaling and proliferation in vitro and induced regression of KRASG12C-mutant tumors in vivo. MRTX849, now known as adagrasib, was one of the first KRAS inhibitors to enter the clinic, and this study included the first-ever reported clinical responses to a KRAS inhibitor, in one patient with non–-small cell lung cancer (NSCLC) and one patient with metastatic colorectal cancer. Preclinical work also pointed to potential resistance mechanisms involving extrinsic regulation of KRAS nucleotide cycling and activation of bypass pathways and suggested potential combination treatment strategies that are currently being evaluated in clinical trials. Early clinical trial results with KRASG12C inhibitor monotherapy suggest that partial responses can be achieved, particularly in NSCLC, but that responses are relatively short-lived and less frequent in patients with colorectal cancer. A preclinical study suggested that the high basal EGFR activity in colorectal cancer cells compared with NSCLC cells limits the activity of KRASG12C inhibitors in this setting, and the first report of clinical resistance to KRASG12C inhibition suggests that acquired secondary KRAS mutations in the switch-II pocket and other polyclonal alterations can converge to reactivate RAS–-MAPK signaling. Though clearly a formidable opponent, KRAS is no longer untouchable.
