Role of KRAS-Nrf2 axis in regulation of metabolic reprogramming in pancreatic cancer: therapeutic implications

The activity of the KRAS oncogene is crucial for the growth of pancreatic cancer. The KRAS oncogene is essential for the development of about 30 % of human tumours, and its targeting is a focus of cancer therapy. The various attempts over the last three decades to develop inhibitors for the protein KRAS or for downstream signaling pathways have not been successful in the clinic, although its importance in cancer has been proven. For this reason, the KRAS oncogene has long been considered as being undruggable. In summary, we have investigated the role of oncogenic KRAS in pancreatic cancer cells. Expression of the oncogene is regulated by G4 structures located in the promoter upstream of TSS, which act as a hub for transcription factors, including hnRNP A1 which has the capacity to unfold G4. In addition to the promoter, the 5'-UTR of KRAS mRNA is also rich in guanine and forms G4 RNA structures. These are recognized by cationic porphyrins: photosensitizers that promote RNA degradation and block translation when irradiated with light. Finally, we have investigated the role of the KRAS-Nrf2 axis in reprogramming the metabolism of pancreatic cancer cells. We found that suppression of KRAS, an approach taken by many scientists, switches the cells to aerobic metabolism, thereby maintaining malignancy. This discovery suggests that besides KRAS, pancreatic cancer progression is arrested if also the creatine and polyamine pathways are inhibited by using combination therapies