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Synthetic lethality as an engine for cancer drug target discovery

Nature Reviews Drug Discovery volume 19, pages 23–38 (2020)Cite this article

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Abstract

The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes). Functional genomic screening based on the genetic concept of synthetic lethality provides an avenue to discover drug targets in all these areas. Although synthetic lethality is not a new idea, recent advances, including CRISPR-based gene editing, have made possible systematic screens for synthetic lethal drug targets in human cancers. Such approaches have broad potential to drive the discovery of the next wave of genetic cancer targets and ultimately the introduction of effective medicines that are still needed for most cancers.

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Fig. 1: Synthetic lethality: a genetic concept reduced to clinical practice.
Fig. 2: PRMT5 and MTAP are a synthetic lethal pair.
Fig. 3: Identifying novel combination targets using CRISPR screening.
Fig. 4: Identifying synthetic lethal drug targets that reverse tumour-intrinsic immune evasion.

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Acknowledgements

The authors thank C.P. Johnson and K. Briggs for helpful discussions and preparation of the manuscript and F. Li and T. Teng for curation and analysis of the Project Achilles dataset. All are full-time employees of and shareholders in Tango Therapeutics.

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  1. Levi A. Garraway

    Present address: Roche/Genentech, South San Francisco, CA, USA

Authors and Affiliations

  1. Tango Therapeutics, Cambridge, MA, USA

    Alan Huang & Barbara Weber

  2. Eli Lilly and Company, Indianapolis, IN, USA

    Levi A. Garraway

  3. UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

    Alan Ashworth

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B.W. and A.H. researched data for article and wrote the article. A.A. contributed to writing the article. All authors contributed substantially to discussion of the content and reviewed and edited the manuscript before submission:

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Correspondence to Barbara Weber.

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Competing interests

A.H. and B.W. are employees of and shareholders in Tango Therapeutics. L.A.G. is an employee of and shareholder in Eli Lilly and Company and is a shareholder in Tango Therapeutics. A.A. is a shareholder in Tango Therapeutics, a consultant for AtlasMDX, Third Rock Ventures, Pfizer, ProLynx and Bluestar and a Genentech scientific advisory board member and receives grant support from Sun Pharma and AstraZeneca. Patents on the use of PARP inhibitors held jointly with AstraZeneca that A.A. has benefited from financially (and may do so in the future) through the ICR Rewards to Inventors Scheme include WO2014013231 (A1) — 2014-01-23, US2012135983 (A1) — 2012-05-31, US2012010204 (A1) — 2012-01-12, US2006142231 (A1) — 2006-06-29, WO2008020180 (A2) — 2008-02-21.

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Related links

Cancer Cell Line Encyclopedia: https://portals.broadinstitute.org/ccle

Project Achilles: https://depmap.org/portal/achilles/

Project DRIVE: https://oncologynibr.shinyapps.io/drive/

Project Score: https://score.depmap.sanger.ac.uk/

Glossary

Genetic context

Histology and genetic architecture that define a specific set of cancer patients (for example, patients with BRCA1-mutant ovarian cancer).

Isogenic cell line pairs

Cultured cell lines genetically engineered to have only a single genetic difference between them.

Competitive inhibitors

Small molecules that compete with the substrates or cofactors when binding to the target enzyme, resulting in functional inhibition. By contrast, an uncompetitive inhibitor binds to an enzyme–substrate complex more tightly than to the enzyme alone, also resulting in functional inhibition.

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Huang, A., Garraway, L.A., Ashworth, A. et al. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov 19, 23–38 (2020). https://doi.org/10.1038/s41573-019-0046-z

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