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Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5.
Mavrakis, Konstantinos J; McDonald, E Robert; Schlabach, Michael R; Billy, Eric; Hoffman, Gregory R; deWeck, Antoine; Ruddy, David A; Venkatesan, Kavitha; Yu, Jianjun; McAllister, Gregg; Stump, Mark; deBeaumont, Rosalie; Ho, Samuel; Yue, Yingzi; Liu, Yue; Yan-Neale, Yan; Yang, Guizhi; Lin, Fallon; Yin, Hong; Gao, Hui; Kipp, D Randal; Zhao, Songping; McNamara, Joshua T; Sprague, Elizabeth R; Zheng, Bing; Lin, Ying; Cho, Young Shin; Gu, Justin; Crawford, Kenneth; Ciccone, David; Vitari, Alberto C; Lai, Albert; Capka, Vladimir; Hurov, Kristen; Porter, Jeffery A; Tallarico, John; Mickanin, Craig; Lees, Emma; Pagliarini, Raymond; Keen, Nicholas; Schmelzle, Tobias; Hofmann, Francesco; Stegmeier, Frank; Sellers, William R.
Afiliación
  • Mavrakis KJ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • McDonald ER; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Schlabach MR; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Billy E; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
  • Hoffman GR; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • deWeck A; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
  • Ruddy DA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Venkatesan K; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Yu J; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
  • McAllister G; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Stump M; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • deBeaumont R; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Ho S; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Yue Y; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Liu Y; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Yan-Neale Y; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Yang G; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Lin F; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Yin H; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Gao H; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Kipp DR; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Zhao S; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • McNamara JT; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Sprague ER; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Zheng B; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
  • Lin Y; China Novartis Institutes for Biomedical Research, Shanghai 201203, China.
  • Cho YS; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Gu J; China Novartis Institutes for Biomedical Research, Shanghai 201203, China.
  • Crawford K; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
  • Ciccone D; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Vitari AC; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
  • Lai A; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
  • Capka V; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Hurov K; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Porter JA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Tallarico J; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Mickanin C; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Lees E; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Pagliarini R; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Keen N; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • Schmelzle T; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
  • Hofmann F; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland.
  • Stegmeier F; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.
  • Sellers WR; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.
Science ; 351(6278): 1208-13, 2016 Mar 11.
Article en En | MEDLINE | ID: mdl-26912361
5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Purina-Nucleósido Fosforilasa / Inhibidor p16 de la Quinasa Dependiente de Ciclina / Metionina / Neoplasias Límite: Humans Idioma: En Revista: Science Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Purina-Nucleósido Fosforilasa / Inhibidor p16 de la Quinasa Dependiente de Ciclina / Metionina / Neoplasias Límite: Humans Idioma: En Revista: Science Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos