Abstract
KRASG12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.
Major Finding: KRASG12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.
Mechanism: Cells that escape inhibition have large pools of newly synthesized, rapidly activated KRASG12C.
Impact: Further study of this mechanism is necessary if KRASG12C inhibitors are to elicit durable responses.
Inhibitors of the oncoprotein KRASG12C 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 KRASG12C 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 KRASG12C mutation treated with the covalent KRASG12C 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 KRASG12C-dependent genes; however, some cells appeared to be able to circumvent the effects of KRASG12C inhibition after a relatively short treatment duration. Further experiments implicated EGFR signaling and AURKA as being crucial to KRASG12C-mutant cells' ability escape from ARS1620-induced quiescence. Mechanistically, the ability of some cells to bypass KRASG12C inhibition seemed to be due to the fact that a pool of newly synthesized KRASG12C is able to maintain activity by undergoing nucleotide exchange prior to drug binding. Treatment with ARS1620 thus eliminates cells that lack adequate KRASG12C expression and selects for cells with a large pool of new KRASG12C that can be rapidly activated as a result of upstream signals. In summary, this work elucidates a previously unknown mechanism of resistance to KRASG12C 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.
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