Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer

SIMPLE SUMMARY: KRAS plays an important role in transmitting signals from growth factors on the outside of the cell to the cell nucleus. It regulates cell proliferation, growth, and survival. The activation of KRAS occurs in multiple tumour types, either directly due to a mutation in the KRAS gene or indirectly via other proteins in the pathway. KRAS was considered an undruggable protein due to its smooth surface, but a recent discovery of a specific pocket in its structure has led to the development of several inhibitors that target the G12C mutation. Two of these, sotorasib and adagrasib, have been approved in advanced non-small-cell lung cancer, and others are currently being tested in clinical trials. Cancer cells can limit the effect of KRAS G12C inhibitors by switching on other proteins or through the development of new resistance mutations; therefore, these inhibitors will likely be used in combination with other therapies to treat patients more effectively. ABSTRACT: Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed.