Key Points
• Via cell-based experiments and deep mutational scanning experiments, researchers performed genomic and histologic analysis to determine adagrasib-resistance patterns in 38 patients with KRAS G12C-mutated cancer.
• In total, 17 of 38 patients developed to resistance to adagrasib, via three proposed mechanisms. According to the authors, “The first category includes secondary mutations or amplifications in KRAS, the target of adagrasib; the second, alternative oncogenic alterations that activate the RTK–RAS signaling pathway but do not directly alter KRAS itself; and the third, histologic transformation from lung adenocarcinoma to squamous-cell carcinoma.”
• They added, “We also performed deep mutational scanning screens of KRASG12C missense variants and systematically defined an atlas of KRAS mutations that confer resistance to multiple KRASG12C inhibitors. These studies defined two apparent major mutational mechanisms of resistance directly involving KRASG12C. As observed clinically, mutations within the drug-binding pocket also caused high-level resistance within our variant screening results and validation assays.”
• The authors determined that a variety of on-target and off-target mechanisms can promote the resistance to KRAS G12C inhibitors. Consequently, there is an unmet need for the development of additional KRAS inhibitors with different means of binding, as well as allele specificities. To counter adagrasib or sotorasib resistance, effective combination therapy regimens are required.
• One limitation of the current study was the heterogeneous nature of tumor and ctDNA sequencing platforms utilized to characterize acquired resistance, with future research focusing on consistent sequencing platforms. Another limitation was that the study examined acquired resistance with adagrasib and not sotorasib, thus making it hard to make direct comparisons between the resistance mechanisms of these agents.

Key Points
• Via cell-based experiments and deep mutational scanning experiments, researchers performed genomic and histologic analysis to determine adagrasib-resistance patterns in 38 patients with KRAS G12C-mutated cancer. This study was funded by Mirati Therapeutics.
• In total, 17 of 38 patients developed to resistance to adagrasib, via three proposed mechanisms. According to the authors, “The first category includes secondary mutations or amplifications in KRAS, the target of adagrasib; the second, alternative oncogenic alterations that activate the RTK–RAS signaling pathway but do not directly alter KRAS itself; and the third, histologic transformation from lung adenocarcinoma to squamous-cell carcinoma.”
• They added, “We also performed deep mutational scanning screens of KRASG12C missense variants and systematically defined an atlas of KRAS mutations that confer resistance to multiple KRASG12C inhibitors. These studies defined two apparent major mutational mechanisms of resistance directly involving KRASG12C. As observed clinically, mutations within the drug-binding pocket also caused high-level resistance within our variant screening results and validation assays.”
• The authors determined that a variety of on-target and off-target mechanisms can promote the resistance to KRAS G12C inhibitors. Consequently, there is an unmet need for the development of additional KRAS inhibitors with different means of binding, as well as allele specificities. To counter adagrasib or sotorasib resistance, effective combination therapy regimens are required.
• One limitation of the current study was the heterogeneous nature of tumor and ctDNA sequencing platforms utilized to characterize acquired resistance, with future research focusing on consistent sequencing platforms. Another limitation was that the study examined acquired resistance with adagrasib and not sotorasib, thus making it hard to make direct comparisons between the resistance mechanisms of these agents.