LAUSR

Simple Summary KRAS is the most common oncogene in human cancers and has long been considered ‘‘undruggable’’—that is, until recently, when covalent inhibitors that selectively target KRASG12C substitution were developed. The satisfactory results of multicenter clinical trials has led to the recent approval of therapy with KRASG12C inhibitors. Although KRASG12C allele-specific drugs have greatly improved the clinical outlook for patients with KRASG12C tumors, particularly lung adenocarcinomas, in which the KRASG12C mutant is most prevalent compared with other KRAS mutations, inevitable challenges, such as intrinsic and acquired drug resistance, must be overcome to maximize the efficacy of KRASG12C inhibitor therapy. Recent studies have shown that compensatory signaling pathways, such as the PI3K/AKT/mTOR pathway, and epigenetic reprogramming, e.g., epithelial-to-mesenchymal transition (EMT), are common mechanisms that mediate intrinsic resistance to KRASG12C inhibitors, whereas acquired resistance and ensuing recurrent disease can arise when cancer cells acquire secondary mutations in the KRAS protein that impair the covalent binding of KRASG12C inhibitors. The identification and targeting of KRASG12C inhibitor resistance mechanisms holds promise for novel strategies to effectively treat patients with KRASG12C-mutant cancers. Abstract KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.