KRAS mutations in advanced non-small cell lung cancer: From biology to novel therapeutic strategies

Kristen rat sarcoma viral oncogene homolog ( KRAS ) mutations play a major role in the carcinogenesis of many types of solid tumors including non-small cell lung cancer (NSCLC). Among KRAS mutations, p.G12C single-nucleotide variant ( KRAS G12C ) is the most frequently reported in NSCLC patients, with a prevalence of about 12–13 %. For many decades, KRAS mutations including KRAS G12C were considered “undruggable” because of the lack of effective and well-tolerated selective therapies. Noteworthy, CodeBreaK100 and KRYSTAL-1 clinical trials have recently demonstrated that sotorasib and adagrasib, two novel selective KRAS G12C inhibitors, have clinical activity with acceptable adverse-event profile for the treatment of advanced NSCLC patients with KRAS G12C mutation. On the other hand, no selective therapies are approved for the treatment of advanced NSCLC patients with non-G12C KRAS mutations. As a result, these patients receive the same treatments as those without KRAS mutations. In this paper, we describe the role of KRAS mutations in NSCLC focusing on the clinical and molecular characteristics which potentially identify specific subtypes of NSCLC patients based on different KRAS mutations. We also provide an overview of the main clinical trials testing novel selective KRAS G12C inhibitors as well as novel potential therapeutic strategies for NSCLC patients with non-G12C KRAS mutations. • KRAS mutations are the most frequent oncogene alterations reported in NSCLC patients. • Sotorasib and adagrasib turned KRAS G12C mutation from “undraggable” to “druggable”. • No effective and well-tolerated selective therapies are available for NSCLC patients with non-G12C KRAS mutations. • NSCLC patients may be characterized by specific clinical-molecular characteristics based on different KRAS mutations. • Many strategies targeting KRAS mutant proteins are under investigation for NSCLC patients KRAS mutations including non-G12C.