Functional exploration of colorectal cancer genomes using Drosophila

Bangi, E., Murgia, C., Teague, A. G.S., Sansom, O. J. and Cagan, R. L. (2016) Functional exploration of colorectal cancer genomes using Drosophila. Nature Communications, 7, 13615. (doi: 10.1038/ncomms13615) (PMID:27897178) (PMCID:PMC5141297)

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.

• Item Type: Articles
• Additional Information: This work was supported by NIH grants R01-CA109730, R01-CA084309 and U54OD020353. O.J.S. and C.M. were funded by a CRUK core grant and an ERC investigator grant.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cagan, Professor Ross and Murgia, Dr Claudio and Sansom, Professor Owen
• Authors: Bangi, E., Murgia, C., Teague, A. G.S., Sansom, O. J., and Cagan, R. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Authors 2016
• First Published: First published in Nature Communications 7:13615
• Publisher Policy: Reproduced under a Creative Commons license