Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers

SIMPLE SUMMARY: Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are the most common alterations in non-small cell lung cancer (NSCLC); they are generally linked to smoking history and are typical of the lung adenocarcinoma (AC) subtype. The clinical relevance of KRAS mutations in NSCLC was generally low or null until a few years ago. What is now emerging is that KRAS-mutant lung AC patients are generally associated with poorer survival. However, the approval of Sotorasib, a KRAS inhibitor, improved the survival of a previously untargetable KRAS-mutant lung AC group. Furthermore, new approaches targeting KRAS are under development. Starting from the description of the biology of KRAS-mutant NSCLC, the present review focuses on the clinical aspects of KRAS mutations in NSCLC. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will also be discussed. ABSTRACT: In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.