Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation

Noritaka Tanaka, Jessica J. Lin, Chendi Li, Meagan B. Ryan, Junbing Zhang, Lesli A.Kiedrowski, Alexa G. Michel, Mohammed U. Syed, Katerina A. Fella, Mustafa Sakhi, Islam Baiev, Dejan Juric, Justin F. Gainor, Samuel J. Klempner, Jochen K. Lennerz, Giulia Siravegna, Liron Bar-Peled, Aaron N. Hata, Rebecca S. Heist, Ryan B. Corcoran


Cancer Discov, 10.1158/2159-8290.CD-21-0365

This paper is one of the first reports of clinical acquired resistance to mutant-selective KRASG12C(OFF) inhibitors in a patient whose lung cancer progressed despite treatment with adagrasib (MRTX849) monotherapy.  It describes multiple RAS pathway resistance mutations that bypass the effects of three examples of first-generation inhibitors.  It also shows that RM-018, a representative KRASG12C-selective inhibitor from Revolution Medicines’ new class of RAS(ON) inhibitors, retains potent inhibitory activity against tumor cells harboring dual KRASG12C/Y92D mutations that are deeply resistant to the RAS(OFF) inhibitor class.  We believe that RAS(ON) inhibitors that are on track to enter the clinic, including RMC-6291 and RMC-6236, have the potential to overcome multiple resistance mechanisms identified in this report and to improve patient outcomes.


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