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Chemical strategies to overcome resistance against targeted anticancer therapeutics

Nature Chemical Biology volume 16, pages 817–825 (2020)Cite this article

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Abstract

Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.

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Fig. 1: Strategies to overcome resistance against molecularly targeted therapeutics.
Fig. 2: Overcoming resistance by designing inhibitors with distinct binding modes.
Fig. 3: Inhibitors with non-overlapping resistance profiles to overcome drug resistance.
Fig. 4: Bivalent inhibitors to overcome drug resistance.
Fig. 5: Schematic of PROTAC and collateral sensitivity strategies.

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Acknowledgements

The authors would like to thank NIH/NIGMS for funding (R35 GM130234-01). R.P. is grateful to the Tri-Institutional Program in Chemical Biology for support. The authors regret any omissions of prior work due to limits on space and the number of citations.

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  1. Rudolf Pisa

    Present address: Department of Cell Biology, Harvard Medical School, Boston, MA, USA

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  1. Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY, USA

    Rudolf Pisa & Tarun M. Kapoor

  2. Tri-Institutional PhD Program in Chemical Biology, The Rockefeller University, New York, NY, USA

    Rudolf Pisa

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Pisa, R., Kapoor, T.M. Chemical strategies to overcome resistance against targeted anticancer therapeutics. Nat Chem Biol 16, 817–825 (2020). https://doi.org/10.1038/s41589-020-0596-8

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