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Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer
Meifang Yu, … , Anirban Maitra, Cullen M. Taniguchi
Meifang Yu, … , Anirban Maitra, Cullen M. Taniguchi
Published August 22, 2019; First published July 23, 2019
Citation Information: JCI Insight. 2019;4(16):e126915. https://doi.org/10.1172/jci.insight.126915.
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Categories: Research Article Gastroenterology Oncology

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth; however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to the oncogenicity of PDAC, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin-related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a 2-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared with vehicle. We found that the chief tumor-suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.

Authors

Meifang Yu, Nicholas D. Nguyen, Yanqing Huang, Daniel Lin, Tara N. Fujimoto, Jessica M. Molkentine, Amit Deorukhkar, Ya’an Kang, F. Anthony San Lucas, Conrad J. Fernandes, Eugene J. Koay, Sonal Gupta, Haoqiang Ying, Albert C. Koong, Joseph M. Herman, Jason B. Fleming, Anirban Maitra, Cullen M. Taniguchi

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