Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors

Vaziri-Gohar, A. et al. (2022) Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors. Nature Cancer, 3(7), pp. 852-865. (doi: 10.1038/s43018-022-00393-y) (PMID:35681100) (PMCID:PMC9325670)

Abstract

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Karim, Ms Saadia
• Authors: Vaziri-Gohar, A., Cassel, J., Mohammed, F. S., Zarei, M., Hue, J. J., Hajihassani, O., Graor, H. J., Srikanth, Y. V.V., Karim, S. A., Abbas, A., Prendergast, E., Chen, V., Katayama, E. S., Dukleska, K., Khokhar, I., Andren, A., Zhang, L., Wu, C., Erokwu, B., Flask, C. A., Zarei, M., Wang, R., Rothermel, L. D., Romani, A. M.P., Bowers, J., Getts, R., Tatsuoka, C., Morton, J. P., Bederman, I., Brunengraber, H., Lyssiotis, C. A., Salvino, J. M., Brody, J. R., and Winter, J. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Cancer
• Publisher: Nature Research
• ISSN: 2662-1347
• ISSN (Online): 2662-1347
• Published Online: 09 June 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Cancer 3(7): 852-865
• Publisher Policy: Reproduced under a Creative Commons License