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- W4362560710 abstract "<div>Abstract<p>Mutant-selective KRAS<sup>G12C</sup> inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in <i>KRAS</i><sup>G12C</sup>-mutant cancers, including non–small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS<sup>G12C</sup> inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with <i>KRAS</i><sup>G12C</sup> NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (<i>KRAS, NRAS, BRAF, MAP2K1</i>), all of which converge to reactivate RAS–MAPK signaling. Notably, a novel <i>KRAS</i><sup>Y96D</sup> mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein–drug interactions and confers resistance to these inhibitors in engineered and patient-derived <i>KRAS</i><sup>G12C</sup> cancer models. Interestingly, a novel, functionally distinct tricomplex KRAS<sup>G12C</sup> active-state inhibitor RM-018 retained the ability to bind and inhibit KRAS<sup>G12C/Y96D</sup> and could overcome resistance.</p>Significance:<p>In one of the first reports of clinical acquired resistance to KRAS<sup>G12C</sup> inhibitors, our data suggest polyclonal RAS–MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRAS<sup>G12C</sup> inhibitor.</p><p><i>See related commentary by Pinnelli and Trusolino, p. 1874</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1861</i></p></div>" @default.
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- W4362560710 date "2023-04-03" @default.
- W4362560710 modified "2023-10-17" @default.
- W4362560710 title "Data from Clinical Acquired Resistance to KRAS<sup>G12C</sup> Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation" @default.
- W4362560710 doi "https://doi.org/10.1158/2159-8290.c.6549266" @default.
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