دورية أكاديمية
Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.
| العنوان: | Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover. |
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| المؤلفون: | Davoli T; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA., Mengwasser KE; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA., Duan J; Department of Neurobiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.; Department of Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, Connecticut 06511, USA., Chen T; Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA., Christensen C; Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA., Wooten EC; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA., Anselmo AN; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA., Li MZ; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA., Wong KK; Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA., Kahle KT; Department of Neurobiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.; Department of Cellular and Molecular Physiology, Centers for Mendelian Genomics, Yale School of Medicine, New Haven, Connecticut 06511, USA., Elledge SJ; Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. |
| المصدر: | Genes & development [Genes Dev] 2016 Dec 15; Vol. 30 (24), pp. 2684-2695. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 8711660 Publication Model: Print Cited Medium: Internet ISSN: 1549-5477 (Electronic) Linking ISSN: 08909369 NLM ISO Abbreviation: Genes Dev Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory Press Original Publication: [Cold Spring Harbor, N.Y.] : Cold Spring Harbor Laboratory in association with the Genetical Society of Great Britain, [c1987- |
| مواضيع طبية MeSH: | Gene Expression Regulation, Neoplastic*, Colorectal Neoplasms/*enzymology , Colorectal Neoplasms/*genetics , Phosphatidylinositol 3-Kinases/*genetics , Phosphatidylinositol 3-Kinases/*metabolism , Signal Transduction/*genetics, Animals ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/physiopathology ; Genomics ; HCT116 Cells ; HEK293 Cells ; Humans ; Mice ; Mutation ; Proteasome Endopeptidase Complex/genetics ; Ribosomes/genetics |
| مستخلص: | Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors. (© 2016 Davoli et al.; Published by Cold Spring Harbor Laboratory Press.) |
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| معلومات مُعتمدة: | R01 CA140594 United States CA NCI NIH HHS; T32 GM007753 United States GM NIGMS NIH HHS; U01 CA199252 United States CA NCI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS |
| فهرسة مساهمة: | Keywords: PI3K; genetics screen; synthetic lethality |
| المشرفين على المادة: | EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 3.4.25.1 (Proteasome Endopeptidase Complex) |
| تواريخ الأحداث: | Date Created: 20170115 Date Completed: 20170627 Latest Revision: 20190107 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5238728 |
| DOI: | 10.1101/gad.290122.116 |
| PMID: | 28087713 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1549-5477 |
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| DOI: | 10.1101/gad.290122.116 |