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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1617922114

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.

Publication TypeJournal Article
Year of Publication2017
AuthorsIlic, N, Birsoy, K, Aguirre, AJ, Kory, N, Pacold, ME, Singh, S, Moody, SE, DeAngelo, JD, Spardy, NA, Freinkman, E, Weir, BA, Tsherniak, A, Cowley, GS, Root, DE, Asara, JM, Vazquez, F, Widlund, HR, Sabatini, DM, Hahn, WC
JournalProc Natl Acad Sci U S A
Date Published2017 Apr 25

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD+ regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD+/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28396387
PubMed Central IDPMC5410781
Grant ListK22 CA193660 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P01 CA142536 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States