Advances in KRAS-Targeted Therapies for Pancreatic Cancer

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing globally, and PDAC remains one of the deadliest malignancies, primarily because of late-stage presentation at diagnosis and limited effective therapies. KRAS mutations are present in approximately 88-92% of PDAC cases, making KRAS an important therapeutic target in PDAC, despite its long-standing historical classification as being "undruggable." This review comprehensively examines the role of KRAS in pancreatic cancer and summarizes both indirect and direct KRAS-targeted therapeutic strategies, including downstream pathway inhibition, metabolic targeting, and emerging direct KRAS inhibitors. The ongoing clinical trials are essential for establishing the efficacy of these emerging therapies, which are poised to gradually transition into clinical practice and ultimately improve patient outcomes. A major challenge with KRAS-targeted therapy is drug resistance, which occurs through both on-target and bypass mechanisms, but emerging combination strategies targeting parallel pathways show promise. Combination approaches involving chemotherapy, immunotherapy, PRMT5 inhibition, and tumor microenvironment targeting are being actively studied to overcome resistance. Overall, KRAS-directed therapies represent a significant and evolving advancement with the potential to improve outcomes in pancreatic cancer.