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Non-genetic mechanisms of therapeutic resistance in cancer

Abstract

Therapeutic resistance continues to be an indominable foe in our ambition for curative cancer treatment. Recent insights into the molecular determinants of acquired treatment resistance in the clinical and experimental setting have challenged the widely held view of sequential genetic evolution as the primary cause of resistance and brought into sharp focus a range of non-genetic adaptive mechanisms. Notably, the genetic landscape of the tumour and the non-genetic mechanisms used to escape therapy are frequently linked. Remarkably, whereas some oncogenic mutations allow the cancer cells to rapidly adapt their transcriptional and/or metabolic programme to meet and survive the therapeutic pressure, other oncogenic drivers convey an inherent cellular plasticity to the cancer cell enabling lineage switching and/or the evasion of anticancer immunosurveillance. The prevalence and diverse array of non-genetic resistance mechanisms pose a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes. In this Perspective we discuss the key principles of non-genetic therapy resistance in cancer. We provide a perspective on the emerging data from clinical studies and sophisticated cancer models that have studied various non-genetic resistance pathways and highlight promising therapeutic avenues that may be used to negate and/or counteract the non-genetic adaptive pathways.

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Fig. 1: Interpretation of mechanisms of resistance are influenced by the resolution of the technology.
Fig. 2: Models of genetic and non-genetic therapy resistance.
Fig. 3: Mechanisms of transient and stable non-genetic resistance.
Fig. 4: Cell of origin and genetic composition influence mechanisms of resistance.
Fig. 5: Cellular plasticity as a mechanism to evade anticancer immunosurveillance.
Fig. 6: Potential therapeutic strategies to counteract non-genetic resistance mechanisms.

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Acknowledgements

The authors thank all the members of the J.-C.M., S.-J.D. and M.A.D laboratories for helpful discussions related to the concepts presents in this Perspective. The authors thank N. Dawson for help with figure construction and graphical illustrations. The authors thank the following funders for support: Cancer Council Victoria for a Sir Edward Dunlop Research Fellowship and Howard Hughes Medical Institute for an international research scholarship (M.A.D) and CSL for a CSL Centenary Fellowship (S.-J.D).

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All authors made substantial contributions to researching data for the article, the discussion of content, writing of the manuscript and editing of it before final submission.

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Correspondence to Jean-Christophe Marine or Sarah-Jane Dawson or Mark A. Dawson.

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M.A.D. has been a member of advisory boards for Cancer Therapeutics CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of the advisory board for AstraZeneca. The S.-J.D. laboratory has received research funding from Genentech. The M.A.D. and S.-J.D. laboratories receive research funding from Cancer Therapeutics CRC. J.-C.M. declares no competing interests.

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Nature Reviews Cancer thanks J. Carroll, U. McDermott and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Marine, JC., Dawson, SJ. & Dawson, M.A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer 20, 743–756 (2020). https://doi.org/10.1038/s41568-020-00302-4

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