Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors

Background Mutant-selective inhibitors of KRASG12C (KRASG12Ci) have demonstrated efficacy in KRASG12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRASG12Ci and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms. Methods To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from postprogression cell-free DNA samples in patients treated with KRASG12Ci at two United States cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors. Results A total of 143 patients were analyzed. Most patients had non-small-cell lung cancer (NSCLC, n = 68) or colorectal cancer (CRC, n = 58) and were treated with single-agent KRASG12Ci (n = 109) or combined with anti-EGFR antibodies (n = 30). RAS/MAPK alterations emerged in 46% of patients (n = 66), with 39% developing one or more new KRAS alterations (n = 56) and 23% (n = 33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS-activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%), and NRAS/HRAS mutations (8%). Notably, the proportion of patients with one or more acquired RAS/MAPK alteration was significantly higher in CRC compared with NSCLC (69% versus 26%, P KRAS-activating mutations, and the RAS(ON) multiselective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations. Conclusions Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.