2. Academic Validation
  3. Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells

Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells

  • Biochem Biophys Res Commun. 2021 Sep 24;571:118-124. doi: 10.1016/j.bbrc.2021.07.070.
Selahattin C Ozcan 1,  Aydan Mutlu 2,  Tugba H Altunok 3,  Yunus Gurpinar 3,  Aybike Sarioglu 3,  Sabire Guler 4,  Robertino J Muchut 5,  Alberto A Iglesias 5,  Serap Celikler 2,  Paul M Campbell 6,  Abdullah Yalcin 7
Affiliations

Affiliations

  • 1 Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, 34450, Turkey.
  • 2 Department of General Biology, School of Arts & Science, Bursa Uludag University, Bursa, 16059, Turkey.
  • 3 Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey.
  • 4 Department of Histology & Embryology, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey.
  • 5 Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of the Littoral, Santa Fe, 3000, Argentina.
  • 6 The Marvin and Concetta Greenberg Pancreatic Cancer Institute, Cancer Signaling & Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
  • 7 Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey. Electronic address: ayalcin@uludag.edu.tr.
PMID: 34325126 DOI: 10.1016/j.bbrc.2021.07.070
Abstract

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.

Keywords

AZ PFKFB3 26; CB-839; GLS1; KRAS; PFKFB3; Pancreatic ductal adenocarcinoma.

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