The great escape: tumour cell plasticity in resistance to targeted therapy

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Abstract

The success of targeted therapies in cancer treatment has been impeded by various mechanisms of resistance. Besides the acquisition of resistance-conferring genetic mutations, reversible mechanisms that lead to drug tolerance have emerged. Plasticity in tumour cells drives their transformation towards a phenotypic state that no longer depends on the drug-targeted pathway. These drug-refractory cells constitute a pool of slow-cycling cells that can either regain drug sensitivity upon treatment discontinuation or acquire permanent resistance to therapy and drive relapse. In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in various cancers, ranging from prostate and lung adenocarcinoma to melanoma and basal cell carcinoma. Our understanding of the mechanisms that control this phenotypic switch has also expanded, revealing the crucial role of reprogramming factors and chromatin remodelling. Further deciphering the molecular basis of tumour cell plasticity has the potential to contribute to new therapeutic strategies which, combined with existing anticancer treatments, could lead to deeper and longer-lasting clinical responses.

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Fig. 1: Distinct scenarios for establishment of minimal residual disease.
Fig. 2: From drug tolerance to drug resistance.
Fig. 3: Strategies to therapeutically target cell plasticity.

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Acknowledgements

The authors thank Felipe de Sousa e Melo, Ciara Metcalfe, Xin Ye and Bob Yauch for their valuable comments and suggestions on the manuscript. We also thank Allison Bruce for drawing the figures.

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S.B. and F.J.d.S. researched data for the article, provided substantial contribution to discussions of the content, wrote the article, and reviewed and edited the manuscript before submission.

Correspondence to Frederic J. de Sauvage.

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The authors are employees of Genentech and own shares of Roche.

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Glossary

Complete response

Reduction in tumour burden measured by radiological imaging or biopsy typically corresponding to at least 99% decrease.

Minimal residual disease

(MRD). Tumour cells that remain once a patient has achieved complete response as measured through radiological imaging or biopsy.

Apical–basal polarity

Polarity typical of epithelial cells, in which the apical surface faces the lumen and the basal side faces the basement membrane.

Transdetermination

The process of lineage conversion, in which a tissue-specific progenitor cell population transforms into the progenitor cell population of a distinct tissue.

Cell lineage

Developmental history of a differentiated cell tracing its cellular origins.

Transdifferentiation

Direct conversion of one differentiated cell type into another without going through a progenitor state.

Ferroptosis

Type of programmed cell death that is dependent on iron and characterized by the accumulation of lipid peroxide chemical species.

Dedifferentiation

The process of lineage reversion in which differentiated cells acquire features of more immature cells within the same lineage.

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