Newly Synthesized KRAS^G12C Mediates Escape from KRAS^G12C Inhibition

Inhibitors of the oncoprotein KRAS^G12C are currently in phase I clinical trials, with preliminary data suggesting that the drugs are effective in some patients with lung adenocarcinoma. Possible resistance mechanisms to KRAS^G12C inhibitors, which selectively bind and trap the mutant protein in its inactive state, are not yet known. To investigate this, Xue, Zhao, and colleagues performed single-cell RNA-sequencing analyses on cells from three lung cancer lines harboring the KRAS^G12C mutation treated with the covalent KRAS^G12C inhibitor ARS1620 for zero, four, 24, or 72 hours. These experiments revealed that, shortly after treatment initiation, most cells were sequestered in a quiescent state with low expression of KRAS^G12C-dependent genes; however, some cells appeared to be able to circumvent the effects of KRAS^G12C inhibition after a relatively short treatment duration. Further experiments implicated EGFR signaling and AURKA as being crucial to KRAS^G12C-mutant cells' ability escape from ARS1620-induced quiescence. Mechanistically, the ability of some cells to bypass KRAS^G12C inhibition seemed to be due to the fact that a pool of newly synthesized KRAS^G12C is able to maintain activity by undergoing nucleotide exchange prior to drug binding. Treatment with ARS1620 thus eliminates cells that lack adequate KRAS^G12C expression and selects for cells with a large pool of new KRAS^G12C that can be rapidly activated as a result of upstream signals. In summary, this work elucidates a previously unknown mechanism of resistance to KRAS^G12C inhibitors and suggests that further study into ways to quash this mechanism are necessary to ensure that responses to this new class of drugs are durable.

Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 2020;577:421–5.

• ©2020 American Association for Cancer Research.