title: Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Davoli
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Mengwasser
authors.affiliation: 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.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Duan
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Christensen
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Wooten
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Anselmo
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Mamie Z
authors.initials: MZ
authors.lastname: Li
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012270:Ribosomes / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex
keywords: PI3K; genetics screen; synthetic lethality