The Role of KRAS in Non-Small Cell Lung Cancer: From Molecular Background to Precision Medicine

KRAS is one of the most frequently altered oncogenes in non-small cell lung cancer (NSCLC), playing a pivotal role in tumour initiation, progression, and therapeutic response. This review summarises the current understanding of the molecular mechanisms underlying KRAS-driven NSCLC, with particular emphasis on signalling pathways, genetic alterations, and their clinical implications. We discuss the spectrum of KRAS mutations and polymorphisms, highlighting their impact on disease biology, prognosis, and treatment outcomes. In addition, the review explores the contribution of epigenetic regulation to KRAS-mediated oncogenesis, focusing on the roles of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as well as post-translational modifications of the KRAS protein, such as methylation, phosphorylation, ubiquitination, nitrosylation, and acetylation. Recent advances in the development of KRAS-targeted therapies are presented, including mutation-specific and pan-KRAS inhibitors. Furthermore, we discuss combination treatment approaches designed to overcome intrinsic and acquired resistance by targeting complementary signalling pathways or modulating the tumour microenvironment. Collectively, this review highlights the complexity of KRAS biology in NSCLC and underscores the importance of integrating molecular, epigenetic, and therapeutic insights to advance precision medicine and improve clinical outcomes.