title: Functional exploration of colorectal cancer genomes using Drosophila.
abstract: The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term 'induced dependence'. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies.
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Annenberg 25-40, New York, New York 10029, USA.
authors.forename: Erdem
authors.initials: E
authors.lastname: Bangi
authors.affiliation: Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Murgia
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Annenberg 25-40, New York, New York 10029, USA.
authors.forename: Alexander G S
authors.initials: AG
authors.lastname: Teague
authors.affiliation: Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK.
authors.forename: Owen J
authors.identifier: 0000-0001-9540-3010
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Annenberg 25-40, New York, New York 10029, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Cagan
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004843:Epistasis, Genetic / Q000187:drug effects; D016678:Genome; D023281:Genomics; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C000614067:AKT activator SC79; D000085:Acetates; D001578:Benzopyrans; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt