Figure 2.
RMC-7977 overcomes acquired resistance to inactive and active state-selective RASG12C inhibitors. A, RMC-7977 monotherapy and RMC-7977/RMC-4998 combination therapy elicit deep and sustained tumor regressions in KRASG12C-mutated NSCLC models with acquired resistance to sotorasib. B, RMC-7977 is active in NSCLC models with acquired in vivo resistance to the RASG12C(ON) inhibitor RMC-4998. C, RMC-7977 overcomes acquired resistance to RMC-4988 driven by secondary alterations in RAS genes. Individual tumors that developed on-treatment resistance to RMC-4988 (KL5shCon RMC-4988 R1-R3 and KP2A RMC-4988 R1-R3) were harvested, processed for WES, and propagated directly in C57BL/6 mice under continuous drug exposure. Mice harboring tumors 450 to 500 mm3 were subsequently treated with RMC-7977 or RMC-7977 plus RMC-4998. Tumor volume growth curves (left) and waterfall plot representation of individual mouse-level best % change in tumor volume (right) are shown. D, OncoPrint depicting somatic genomic alterations (SNVs, indels, and copy number alterations) in the RMC-4988-resistant models and the parental KL5 and KP2 cell lines. Individual tumors from the experiment depicted in D are indicated as R1, R2, and R3.