KRAS Mutations in Cancer: Molecular Insights, Therapeutic Advances, and Strategies to Overcome Resistance

Abstract

KRAS mutations are among the most frequent oncogenic alterations in human cancers, with a particularly high prevalence in pancreatic, colorectal, and lung malignancies. These genetic changes disrupt the normal regulation of cell signaling pathways, leading to sustained proliferation, altered metabolism, and resistance to apoptosis. For decades, KRAS was considered beyond the reach of pharmacological intervention, largely due to its structural complexity and strong nucleotide-binding affinity. Recent scientific progress has challenged this notion, resulting in the approval of selective inhibitors that have changed the management of cancers carrying KRAS mutations. Nevertheless, resistance to these agents continues to emerge through tumor heterogeneity, compensatory signaling, and secondary genetic events. Current research is focused on developing next-generation inhibitors, RNA-based therapies, degraders, and immune-based approaches to address these challenges. In addition, artificial intelligence and advanced drug delivery technologies are expanding the possibilities for therapeutic innovation. Pharmacists and clinicians play a critical role in integrating biomarker testing, therapeutic monitoring, and patient support to optimize treatment outcomes and improve access to targeted therapies. This review examines the molecular basis of KRAS-driven cancers, evaluates the progress of pharmacological strategies, and highlights the ongoing challenges and opportunities for future research and clinical practice.