Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Richard Possemato, Kevin M. Marks, Yoav D. Shaul, Michael E. Pacold, Dohoon Kim, Kıvanç Birsoy, Shalini Sethumadhavan, Hin-Koon Woo, Hyun G. Jang, Abhishek K. Jha, Walter W. Chen, Francesca G. Barrett, Nicolas Stransky, Zhi-Yang Tsun, Glenn S. Cowley, Jordi Barretina, Nada Y. Kalaany, Peggy P. Hsu, Kathleen Ottina, Albert M. Chan, Bingbing Yuan, Levi A. Garraway, David E. Root, Mari Mino-Kenudson, Elena F. Brachtel, Edward M. Driggers and David M. Sabatini ()
Additional contact information
Richard Possemato: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Kevin M. Marks: Agios Pharmaceuticals, 38 Sidney Street
Yoav D. Shaul: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Michael E. Pacold: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Dohoon Kim: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Kıvanç Birsoy: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Shalini Sethumadhavan: Agios Pharmaceuticals, 38 Sidney Street
Hin-Koon Woo: Agios Pharmaceuticals, 38 Sidney Street
Hyun G. Jang: Agios Pharmaceuticals, 38 Sidney Street
Abhishek K. Jha: Agios Pharmaceuticals, 38 Sidney Street
Walter W. Chen: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Francesca G. Barrett: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Nicolas Stransky: Broad Institute of Harvard and MIT, Seven Cambridge Center
Zhi-Yang Tsun: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Glenn S. Cowley: Broad Institute of Harvard and MIT, Seven Cambridge Center
Jordi Barretina: Broad Institute of Harvard and MIT, Seven Cambridge Center
Nada Y. Kalaany: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Peggy P. Hsu: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Kathleen Ottina: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Albert M. Chan: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Bingbing Yuan: Whitehead Institute for Biomedical Research, Nine Cambridge Center
Levi A. Garraway: Broad Institute of Harvard and MIT, Seven Cambridge Center
David E. Root: Broad Institute of Harvard and MIT, Seven Cambridge Center
Mari Mino-Kenudson: Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA
Elena F. Brachtel: Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA
Edward M. Driggers: Agios Pharmaceuticals, 38 Sidney Street
David M. Sabatini: Whitehead Institute for Biomedical Research, Nine Cambridge Center

Nature, 2011, vol. 476, issue 7360, 346-350

Abstract: Serine biosynthesis target in breast cancer An in vivo RNAi screen of metabolic enzymes and transporters is used to identify, among other genes, phosphoglycerate dehydrogenase (PHGDH) as a gene required for breast tumour growth. PHGDH resides in a region of chromosome 1p that is often amplified in breast cancers, leading to PHGDH overexpression. Elevated levels of PHGDH cause increased metabolic flux through the serine synthesis pathway, which in turn contributes significantly to the flux of glutamine to α-ketoglutarate through the tricarboxylic acid cycle. These observations suggest that targeting PHGDH or the serine biosynthesis pathway in general might be of therapeutic value in the subset of breast cancers with high PHGDH expression.

Date: 2011
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DOI: 10.1038/nature10350

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