Abstract
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.
Highlights
Pancreatic cancer is one of the most prevalent cancers and a major cause of cancerrelated death worldwide according to the GLOBOCAN 2018
This review focuses on the mechanism of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mediated metabolic rewiring
Continuous de novo lipogenesis provides cells with essential membrane building blocks, lipid signaling molecules, and post-translational protein modifications to support rapid cell proliferation and growth [105]. This process is characterized by an increased expression and activity of lipogenic enzymes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and acetyl-CoA carboxylase 1 (ACC1) regulated by KRAS [62,102,108,109,110]
Summary
Pancreatic cancer is one of the most prevalent cancers and a major cause of cancerrelated death worldwide according to the GLOBOCAN 2018. Mutations in four major genes including Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein 53 (p53), and SMAD4 significantly contribute to the development of pancreatic cancer [4,5]. Given the treatment challenges and the aggressive nature and lethality of PDAC, further research for new local and systemic therapies focusing on other aspects of the KRAS signaling including its metabolism ought to be exploited. It might provide a whole new approach to PDAC management. The mechanisms by which different pathways contribute to the enhanced general lipid metabolism observed in pancreatic cancer are emphasized, and the potential targets for cancer control are highlighted
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