Mechanisms of resistance to KRAS G12C inhibitors in lung cancer

Glycine to cysteine substitution at codon 12 (G12C) is the most frequent KRAS change in non-small-cell lung cancer (NSCLC), and it occurs in almost 30% of cases. KRAS mutations have been considered undruggable until 2013, and from then to now, FDA has approved only two inhibitors, sotorasib and adagrasib, in 2021 and 2022. Despite great initial expectations, relapse still occurs in NSCLC patients after approximately 6 months of single agent treatment. Cancer resistance utilizes both genetic and non-genetic mechanisms to adapt to drug-induced toxicity, and subsequent selection promotes resistant clone expansion. This thesis takes into consideration some different resistance mechanisms identified in NSCLC and delves into how they could be fought. It demonstrates the emergence of heterogeneous patterns of resistance with multiple subclonal events during G12C inhibitor treatment. Moreover, it unravels the role of unrecognized non-genetic mechanisms underlying resistance to sotorasib. Ultimately, it underlines the importance of drug combinations in order to overcome the appearance of drug resistance.