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Ozcan SC , Mutlu A , Altunok TH , Gurpinar Y , Sarioglu A , Guler S , Muchut RJ , Iglesias AA , Celikler S , Campbell PM , Yalcin A
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells
Biochem Biophys Res Commun. 2021 Jul 26;571 :118-124
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Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.
1090-2104 Ozcan, Selahattin C Mutlu, Aydan Altunok, Tugba H Gurpinar, Yunus Sarioglu, Aybike Guler, Sabire Muchut, Robertino J Iglesias, Alberto A Celikler, Serap Campbell, Paul M Yalcin, Abdullah Journal Article United States Biochem Biophys Res Commun. 2021 Jul 26;571:118-124. doi: 10.1016/j.bbrc.2021.07.070.