Mevalonate pathway in pancreatic ductal adenocarcinoma: Mechanisms driving metabolic and cellular plasticity

The mevalonate pathway plays a crucial role in the metabolic reprogramming of pancreatic ductal adenocarcinoma (PDAC), driving lipid biosynthesis, redox homeostasis, and oncogenic signaling, thereby sustaining tumor progression and therapeutic resistance. Its integration with Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven signaling networks establishes it as a cornerstone of PDAC biology and a promising therapeutic target. The products of the pathway (sterols and isoprenoids) support key processes such as membrane biogenesis, protein prenylation, and immune evasion, facilitating tumor adaptation to the harsh microenvironment. Despite extensive research, therapeutic resistance and metabolic plasticity present considerable challenges in targeting this pathway. This review synthesizes current knowledge regarding the biochemical regulation of the mevalonate pathway in PDAC, its crosstalk with key oncogenic signaling networks, and emerging therapeutic strategies. In addition, we highlight critical knowledge gaps, including the complex regulatory crosstalk of the pathway with oncogenes, tumor suppressors, and nutrient-sensing pathways, and the mechanisms by which metabolic rewiring modulates tumor-immune interactions and therapy resistance. By integrating insights from pre-clinical and clinical studies, we highlighted promising novel combination therapies, including statins, bisphosphonates, and sterol regulatory element-binding protein (SREBP) inhibitors, as well as the potential for precision medicine approaches targeting mevalonate pathway vulnerabilities. Addressing these challenges may provide new avenues for improving therapeutic outcomes in PDAC.