Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?

Abstract

The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.

Key points

  • The first synthetic lethal therapy (poly(ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1-mutant or BRCA2-mutant ovarian and breast cancers) has been approved for clinical use.

  • Cancer-specific alterations in multiple pathways could, in principle, be targeted using synthetic lethality.

  • Attention will need to be paid to the robustness of synthetic lethal effects observed in preclinical models if the optimal level of translation to clinical benefit is to be achieved.

  • New technology (such as CRISPR–Cas9 mutagenesis) and conceptual advances will speed the discovery of new clinically applicable synthetic lethal interactions.

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Fig. 1: Parallel pathway-based synthetic lethality.

Adapted from ref.27, Macmillan Publishers Limited.

Fig. 2: Multiple component pathway-based synthetic lethality.
Fig. 3: Paralogue-based synthetic lethality.

Adapted from ref.132, Macmillan Publishers Limited.

Fig. 4: Collateral synthetic lethality via loss of genetic material.
Fig. 5: Collateral synthetic lethality via complex collapse.

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Acknowledgements

A.A. acknowledges financial support from the Susan G. Komen for the Cure organization, the Breast Cancer Research Foundation and the BRCA Foundation. C.J.L. acknowledges financial support from Cancer Research UK and Breast Cancer Now.

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Both authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Alan Ashworth or Christopher J. Lord.

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A.A. is or has been a consultant of AtlasMDX, Bluestar, Driver, Genentech, Pfizer, Prolynx, Sun Pharma and Third Rock Ventures; has received research support from Sun Pharma; is the co-founder of Tango Therapeutics; and holds patents on the use of poly(ADP-ribose) polymerase (PARP) inhibitors jointly with AstraZeneca, from which he has benefited financially (and may do so in the future) through the Institute of Cancer Research Rewards to Inventors scheme. C.J.L. is or has been a consultant of AstraZeneca, GLG, Guidepoint, Sun Pharma, Third Rock Ventures and Vertex; has received research support from AstraZeneca and Merck KGaA; and holds patents on the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventors scheme.

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Ashworth, A., Lord, C.J. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?. Nat Rev Clin Oncol 15, 564–576 (2018). https://doi.org/10.1038/s41571-018-0055-6

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