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

作者：Jakob M. Riedl, Ferran Fece de la Cruz, W. Marston Linehan, Christine M. Parseghian, Jonathan Kim, Hiroyuki Matsubara, Haley Barnes, Bennett Adam Caughey, Bryanna L. Norden, Alvin A. Morales-Giron, Erich James Kushner, Sara Ehnstrom, H. Nakamura, Preeti Patel, Haley Ellis, Leontios Pappas, A Vakaris, Justin F. Gainor, Scott Kopetz, Samuel J. Klempner, A.R. Parikh, Aaron N. Hata, Rebecca S. Heist, Ryan B. Corcoran · 发表于：Annals of Oncology · 年份：2025 · DOI：10.1016/j.annonc.2025.01.020 · 被引用次数：56 · 研究领域：Protein Kinase Regulation and GTPase Signaling、HER2/EGFR in Cancer Research、Receptor Mechanisms and Signaling

Background Mutant-selective inhibitors of KRAS G12C (KRAS G12C i) have demonstrated efficacy in KRAS G12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRAS G12C i 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 KRAS G12C i 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 KRAS G12C i ( 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 pr...