Resistance to KRAS G12C Inhibition in Non-small Cell Lung Cancer

Purpose of review: Although the recent development of direct KRASG12C inhibitors (G12Ci) has improved outcomes in KRAS mutant cancers, responses occur only in a fraction of patients, and among responders acquired resistance invariably develops over time. Therefore, the characterization of the determinants of acquired resistance is crucial to inform treatment strategies and to identify novel therapeutic vulnerabilities that can be exploited for drug development. Recent findings: Mechanisms of acquired resistance to G12Ci are heterogenous including both on-target and off-target resistance. On-target acquired resistance includes secondary codon 12 KRAS mutations, but also acquired codon 13 and codon 61 alterations, and mutations at drug binding sites. Off-target acquired resistance can derive from activating mutations in KRAS downstream pathway (e.g., MEK1), acquired oncogenic fusions (EML4-ALK, CCDC176-RET), gene level copy gain (e.g., MET amplification), or oncogenic alterations in other pro-proliferative and antiapoptotic pathways (e.g., FGFR3, PTEN, NRAS). In a fraction of patients, histologic transformation can also contribute to the development of acquire resistance. We provided a comprehensive overview of the mechanisms that limit the efficacy of this G12i and reviewed potential strategies to overcome and possibly delay the development of resistance in patients receiving KRAS directed targeted therapies.