Uncovering KRAS-mutant allele-specific biology and vulnerabilities in non-small cell lung cancer

KRAS (Kirsten-Ras) mutations are the most commonly occurring oncogenic drivers in non-small cell lung cancer. Despite the discovery of KRAS inhibitors representing a translational breakthrough for KRAS-driven cancers, resistance remains a major clinical challenge. We believe that to circumvent resistance, an in-depth understanding of the biological differences and therapeutic vulnerabilities specific to KRAS mutations is critical to inform rational combination partners with either mutant-selective or broad-spectrum (K)RAS inhibitors. The present review draws upon insights from both preclinical and clinical studies exploring KRAS-mutant allele-specific behaviours and therapeutic vulnerabilities. We will also highlight studies in which targeting of these vulnerabilities was combined with (K)RAS inhibitors, offering contextual examples of KRAS-mutant allele-tailored therapeutic strategies.