A metabolic switch to the pentose-phosphate pathway induces radiation resistance in pancreatic cancer

• Published in: Radiotherapy and oncology 2025-01, Vol.202, p.110606, Article 110606
• Main Authors: Shimoni-Sebag, Ariel, Abramovich, Ifat, Agranovich, Bella, Massri, Rami, Stossel, Chani, Atias, Dikla, Raites-Gurevich, Maria, Yizhak, Keren, Golan, Talia, Gottlieb, Eyal, Lawrence, Yaacov Richard
• Format: Article
• Language: English
• Subjects: 6-Aminonicotinamide - pharmacology; Animals; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - radiotherapy; Cell Line, Tumor; DNA damage; Glycolysis; Humans; Metabolic reprogramming; Mice; Mice, Nude; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - radiotherapy; Pentose Phosphate Pathway; Radiation resistance; Radiation therapy; Radiation Tolerance; Xenograft Model Antitumor Assays
• ISSN: 0167-8140; 1879-0887; 1879-0887
• DOI: 10.1016/j.radonc.2024.110606

[Display omitted] •Novel model of radioresistance identified in pancreatic cancer.•Radioresistant PDAC cells display metabolic reprogramming.•Elevated glycolysis and reduced TCA cycle and OXPHOS in radioresistant PDAC cells.•Increased flux to the PPP and elevated GSH in radioresistant PDAC cells.•Inhibition of the PPP synergizes with radiation in-vivo.•PPP inhibition combined with RT synergistically reduces PDAC tumor growth. Pancreatic ductal adenocarcinoma (PDAC) is remarkably resistant to standard modalities, including radiotherapy. We hypothesized that metabolic reprogramming may underlie PDAC radioresistance, and moreover, that it would be possible to exploit these metabolic changes for therapeutic intent. We established two matched models of radioresistant PDAC cells by exposing the AsPC-1 and MIAPaCa-2 human pancreatic cancer cells to incremental doses of radiation. The metabolic profile of parental and radioresistant cells was investigated using Nanostring technology, labeled-glucose tracing by liquid chromatography-mass spectrometry, Seahorse analysis and exposure to metabolic inhibitors. The synergistic effect of radiation combined with a pentose-phosphate pathway inhibitor, 6-aminonicotinamide (6-AN) was evaluated in a xenograft model established by subcutaneous injection of radioresistant-AsPC-1 cells into nude mice. The radioresistant cells overexpressed pyruvate dehydrogenase kinase (PDK) and consistently, displayed increased glycolysis and downregulated the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Metabolic flux through the pentose-phosphate pathway (PPP) was increased, as were levels of reduced glutathione; pharmacological inhibition of the PPP dramatically potentiated radiation-induced cell death. Furthermore, the combined treatment of radiation with the PPP inhibitor 6-AN synergistically inhibited tumor growth in-vivo. We provide a mechanistic understanding of the metabolic changes that underlie radioresistance in PDAC. Furthermore, we demonstrate that pancreatic cancer cells can be re-sensitized to radiation via metabolic manipulation, in particular, inhibition of the PPP. Exploitation of the metabolic vulnerabilities of radioresistant pancreatic cancer cells constitutes a new approach to pancreatic cancer, with a potential to improve clinical outcomes.