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Synthetic lethal approaches to breast cancer therapy

Abstract

The promise of personalized therapy for breast cancer is that therapeutic efficacy will be increased while toxic effects are reduced to a minimum. To achieve this goal, there is now an emphasis on the design of therapies that are based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. However, identifying targets for personalized therapies in breast cancer is challenging. Here, we describe how biological concepts such as synthetic lethality and oncogene addiction can be used to identify new therapeutic targets and approaches. We discuss the current clinical developments in implementing synthetic lethality therapies, and highlight new ways in which this approach could be used to target specific subsets of breast cancer.

Key Points

  • Biological concepts such as oncogene addiction and synthetic lethality can be used to design novel approaches to breast cancer treatment

  • Preclinical work has firmly established synthetic lethality between dysfunction of the tumor suppressor genes BRCA1 and BRCA2 and inhibition of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP)

  • Clinical trials in BRCA mutation carriers with breast cancer suggest that the BRCA/PARP synthetic lethality has considerable promise

  • It is as yet unclear which fraction of sporadic breast cancers, if any, might respond to PARP inhibitors; trials that encompass mechanism-based biomarkers are now required

  • Synthetic lethal interactions can be rapidly identified in the laboratory using high-throughput RNA interference and chemical and drug screening

  • The concept of synthetic lethality could also be used to address pharmacologically intractable targets in breast cancer

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Figure 1: Synthetic lethality.
Figure 2: RAD51 foci formation as a biomarker for HR function and sensitivity to PARP inhibitors.
Figure 3: Tools for discovering synthetic lethal relationships.

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Acknowledgements

We thank members of the Gene Function Laboratory and clinical collaborators for sharing insight and/or preliminary data. Work in our laboratory is funded by Breakthrough Breast Cancer, CRUK, AACR, BCRF, The Breast Cancer Campaign and The Komen Foundation.

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All the authors contributed to discussion of content for the article, researched data to include in the manuscript, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments.

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Correspondence to Alan Ashworth.

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A. Ashworth and C. J. Lord are patent applicants/holders in association with the Institute of Cancer Research and AstraZeneca Rewards to Inventors Scheme. F. L. Rehman declares no competing interests.

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Rehman, F., Lord, C. & Ashworth, A. Synthetic lethal approaches to breast cancer therapy. Nat Rev Clin Oncol 7, 718–724 (2010). https://doi.org/10.1038/nrclinonc.2010.172

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