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Abstract #0912

Down-regulation of phospholipid biosynthesis is a unique metabolic feature of mutant IDH1 gliomas mediated by autophagy of the endoplasmic reticulum

Pavithra Viswanath1, Russell O Pieper2, Joanna J Phillips2, and Sabrina M Ronen1

1Radiology, University of California San Francisco, San Francisco, CA, United States, 2Neurosurgery, University of California San Francisco, San Francisco, CA, United States

Virtually every cancer studied so far shows elevated choline and ethanolamine phospholipid metabolism, which has emerged as a metabolic hallmark of cancer. Here, we show that, unusually, low-grade gliomas carrying a mutation in isocitrate dehydrogenase 1 (IDHmut) down-regulate phosphatidylcholine and phosphatidylethanolamine biosynthesis and steady-state levels. Mechanistically, this down-regulation is mediated via autophagic degradation of the endoplasmic reticulum, the site of phospholipid biosynthesis. Importantly, the autophagy inhibitor chloroquine restores phospholipid levels and abrogates IDHmut tumor growth, identifying a potential therapeutic opportunity. Thus, our study demonstrates that IDHmut gliomas uniquely down-regulate phospholipid biosynthesis and that this phenomenon can be exploited for therapy.

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