Combinatorial drug therapy for cancer in the post-genomic era

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Abstract

Over the past decade, whole genome sequencing and other 'omics' technologies have defined pathogenic driver mutations to which tumor cells are addicted. Such addictions, synthetic lethalities and other tumor vulnerabilities have yielded novel targets for a new generation of cancer drugs to treat discrete, genetically defined patient subgroups. This personalized cancer medicine strategy could eventually replace the conventional one-size-fits-all cytotoxic chemotherapy approach. However, the extraordinary intratumor genetic heterogeneity in cancers revealed by deep sequencing explains why de novo and acquired resistance arise with molecularly targeted drugs and cytotoxic chemotherapy, limiting their utility. One solution to the enduring challenge of polygenic cancer drug resistance is rational combinatorial targeted therapy.

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Figure 1: History of combination therapy for cancer.
Figure 2: Components of iterative computational approaches for identifying drug combinations.
Figure 3: Evolutionary model of clonal heterogeneity.
Figure 4: Network-based computational models.
Figure 5: The evolution of strategies and technologies for evaluating drug combinations.

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Acknowledgements

The authors acknowledge core support to the Cancer Therapeutics Unit from Cancer Research UK (program grant C309/A8274); P.W. is a Cancer Research UK Life Fellow (C309/8992). P.W. and U.B. acknowledge Experimental Cancer Centre (ECMC) Funding to the Drug Development Unit from Cancer Research UK, National Institute of Health Research (NIHR) and the Department of Health. All authors acknowledge funding from the National Health Service to the NIHR Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden Hospital. We thank V. Cornwell and A. Ford for excellent administrative support and our colleagues for helpful discussion.

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Correspondence to Bissan Al-Lazikani or Udai Banerji or Paul Workman.

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Competing interests

The authors are members of the Institute of Cancer Research (ICR), which has commercial interest in inhibitors of CYP17, HSP90, PI3 Kinase, PKB and histone deacetylase, and operates a 'Rewards to Inventors' scheme. P.W. and ICR colleagues have received research funding from Cougar Biotechnology, Johnson & Johnson, Vernalis, Yamanouchi, Piramed Pharma (acquired by Roche), Astex Pharmaceuticals, AstraZeneca and Chroma Therapeutics. P.W. has been/is a consultant/scientific advisory board member for Novartis, Piramed Pharma, Astex Pharmaceuticals, Chroma Therapeutics, Kudos Pharmaceuticals, Wilex and Nextech Invest.

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Al-Lazikani, B., Banerji, U. & Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol 30, 679–692 (2012) doi:10.1038/nbt.2284

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