Your browser doesn't support javascript.
loading
PIK3CA mutant tumors depend on oxoglutarate dehydrogenase.
Ilic, Nina; Birsoy, Kivanç; Aguirre, Andrew J; Kory, Nora; Pacold, Michael E; Singh, Shambhavi; Moody, Susan E; DeAngelo, Joseph D; Spardy, Nicole A; Freinkman, Elizaveta; Weir, Barbara A; Tsherniak, Aviad; Cowley, Glenn S; Root, David E; Asara, John M; Vazquez, Francisca; Widlund, Hans R; Sabatini, David M; Hahn, William C.
Afiliación
  • Ilic N; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Birsoy K; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
  • Aguirre AJ; Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065.
  • Kory N; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Pacold ME; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
  • Singh S; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
  • Moody SE; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
  • DeAngelo JD; David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.
  • Spardy NA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • Freinkman E; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • Weir BA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
  • Tsherniak A; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
  • Cowley GS; David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.
  • Root DE; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • Asara JM; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • Vazquez F; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Widlund HR; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
  • Sabatini DM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
  • Hahn WC; Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
Proc Natl Acad Sci U S A ; 114(17): E3434-E3443, 2017 04 25.
Article en En | MEDLINE | ID: mdl-28396387
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositol 3-Quinasa Clase I / Complejo Cetoglutarato Deshidrogenasa / Mutación / Proteínas de Neoplasias / Neoplasias Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositol 3-Quinasa Clase I / Complejo Cetoglutarato Deshidrogenasa / Mutación / Proteínas de Neoplasias / Neoplasias Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos