Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer

Simple Summary Cancer is a heterogeneous disease characterized by uncontrollable abnormal cell growth. KRAS plays a crucial role in cell proliferation and differentiation. KRAS mutations are frequently found in many types of cancer, including non-small-cell lung cancer. However, targeting this oncogene has been a real challenge for many years. Recent advances in KRAS targeting have changed the current therapeutic landscape. In this review, we summarize the therapeutic strategies for KRAS-mutated NSCLC with encouraging results and restrictions. Moreover, we present possible combination therapies aiming to achieve individualized treatment.Abstract Kirsten rat sarcoma virus (KRAS) is the most frequently found oncogene in human cancers, including non-small-cell lung cancer (NSCLC). For many years, KRAS was considered "undruggable" due to its structure and difficult targeting. However, the discovery of the switch II region in the KRAS-G12C-mutated protein has changed the therapeutic landscape with the design and development of novel direct KRAS-G12C inhibitors. Sotorasib and adagrasib are FDA-approved targeted agents for pre-treated patients with KRAS-G12C-mutated NSCLC. Despite promising results, the efficacy of these novel inhibitors is limited by mechanisms of resistance. Ongoing studies are evaluating combination strategies for overcoming resistance. In this review, we summarize the biology of the KRAS protein and the characteristics of KRAS mutations. We then present current and emerging therapeutic approaches for targeting KRAS mutation subtypes intending to provide individualized treatment for lung cancer harboring this challenging driver mutation.