KRAS in NSCLC: State of the Art and Future Perspectives

Simple Summary Rat sarcoma virus (RAS) GTP-ase proteins represent a key element in cellular proliferation, growth, and differentiation. Three different isoforms of RAS proteins have been identified to date (KRAS, NRAS, HRAS) and mutations in KRAS are frequently found in human cancers, among which the Non-Small Cell Lung Cancer (NSCLC). In this review we assess molecular, prognostic, and clinico-pathological characteristics of KRAS mutations in NSCLC patients. Next, we present current therapeutic strategies for KRAS mutant NSCLC patients and mechanisms of acquired resistance identified to date. We then focus on the role of immune-checkpoint inhibitors in KRAS mutant NSCLC patients. Finally, we will overview ongoing trials and future needs for this subpopulation cohort. In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.