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Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):E3434-E3443. doi: 10.1073/pnas.1617922114. Epub 2017 Apr 10.

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
2
Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
3
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065.
4
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
5
David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.
6
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
8
Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
9
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; william_hahn@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

2OG; OGDH; PIK3CA; TCA cycle; glycolysis

PMID:
28396387
PMCID:
PMC5410781
DOI:
10.1073/pnas.1617922114
[Indexed for MEDLINE]
Free PMC Article

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