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

This paper is one of the first reports of clinical acquired resistance to mutant-selective KRAS^G12C(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 KRAS^G12C-selective inhibitor from Revolution Medicines’ new class of RAS(ON) inhibitors, retains potent inhibitory activity against tumor cells harboring dual KRAS^G12C/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.