KRAS, A Prime Mediator in Pancreatic Lipid Synthesis through Extra Mitochondrial Glutamine and Citrate Metabolism

Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven pancreatic cancer is very lethal, with a five-year survival rate of <9%, irrespective of therapeutic advances. Different treatment modalities including chemotherapy, radiotherapy, and immunotherapy demonstrated only marginal efficacies because of pancreatic tumor specificities. Surgery at the early stage of the disease remains the only curative option, although only in 20% of patients with early stage disease. Clinical trials targeting the main oncogenic driver, KRAS, have largely been unsuccessful. Recently, global metabolic reprogramming has been identified in patients with pancreatic cancer and oncogenic KRAS mouse models. The newly reprogrammed metabolic pathways and oncometabolites affect the tumorigenic environment. The development of methods modulating metabolic reprogramming in pancreatic cancer cells might constitute a new approach to its therapy. In this review, we describe the major metabolic pathways providing acetyl-CoA and NADPH essential to sustain lipid synthesis and cell proliferation in pancreatic cancer cells.

Automated summary

KRAS-driven pancreatic cancer is highly lethal, with surgery being the only curative option for a small percentage of patients. Treatment targeting KRAS remains largely unsuccessful, despite the identification of global metabolic reprogramming in pancreatic cancer cells. Modulating metabolic pathways may provide a new approach for therapy in pancreatic cancer.