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.
Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK.
Nat Commun. 2016 Nov 29;7:13615. doi: 10.1038/ncomms13615.
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.
人类肿瘤的多基因性质给癌症药物发现带来了根本性的挑战。在这里，我们使用果蝇根据癌症基因组图谱（The Cancer Genome Atlas）中的患者数据生成了 32 种结肠直肠癌的多基因模型。这些模型再现了人类癌症的关键特征，通常是多基因组合的涌现特性。多基因模型，如 ras p53 pten apc，表现出对一系列癌症相关药物的涌现性耐药性。通过详细研究一种药物，我们确定了 PI3K 通路抑制剂 BEZ235 的耐药机制。我们利用这些数据确定了一种组合疗法，通过我们称之为“诱导依赖性”的两步过程来规避这种耐药性，即新兴的通路依赖性和敏感性。这种方法在培养的人类肿瘤细胞、异种移植和结直肠癌的小鼠模型中都有效。这些数据表明，参考癌症基因组的多基因动物模型如何为开发新的靶向治疗方法提供了一种有效的途径。
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