Mutant-selective KRAS G12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRAS G12C -mutant cancers including non-small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRAS G12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a KRAS G12C NSCLC patient who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS-MAPK signaling. Notably, a novel KRAS Y96D 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 patientderived KRAS G12C cancer models. Interestingly, a novel, functionally distinct tri-complex KRAS G12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRAS G12C/Y96D and could overcome resistance. STATEMENT OF SIGNIFICANCEIn one of the first reports of clinical acquired resistance to KRAS G12C 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 G12C inhibitor.Research.

Highlights d Mono-phosphorylation controls RB's association with other proteins d Distinct mono-phosphorylated forms of RB have different transcriptional outputs d RB mono-phosphorylation at S811 promotes NuRDdependent transcriptional repression d Mono-phosphorylation of RB's C-terminal domain enhances expression of OXPHOS genes

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