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  • Perspective
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Evolutionary determinants of curability in cancer

Nature Ecology & Evolution volume 7, pages 1761–1770 (2023)Cite this article

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Abstract

The emergence of drug-resistant cells, most of which have a mutated TP53 gene, prevents curative treatment in most advanced and common metastatic cancers of adults. Yet, a few, rarer malignancies, all of which are TP53 wild type, have high cure rates. In this Perspective, we discuss how common features of curable cancers offer insights into the evolutionary and developmental determinants of drug resistance. Acquired loss of TP53 protein function is the most common genetic change in cancer. This probably reflects positive selection in the context of strong ecosystem pressures including microenvironmental hypoxia. Loss of TP53’s functions results in multiple fitness benefits and enhanced evolvability of cancer cells. TP53-null cells survive apoptosis, and tolerate potent oncogenic signalling, DNA damage and genetic instability. In addition, critically, they provide an expanded pool of self-renewing, or stem, cells, the primary units of evolutionary selection in cancer, making subsequent adaptation to therapeutic challenge by drug resistance highly probable. The exceptional malignancies that are curable, including the common genetic subtype of childhood acute lymphoblastic leukaemia and testicular seminoma, differ from the common adult cancers in originating prenatally from embryonic or fetal cells that are developmentally primed for TP53-dependent apoptosis. Plus, they have other genetic and phenotypic features that enable dissemination without exposure to selective pressures for TP53 loss, retaining their intrinsic drug hypersensitivity.

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Fig. 1: Summary of our model of the biological determinants of curability or intransigence in cancer.
Fig. 2: Imaging hypoxia, angiogenesis and cell loss or survival in curable and intransigent cancers.
Fig. 3: Natural history of ‘curable’ B-cell precursor childhood ALL.

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Acknowledgements

This Perspective is dedicated to the memory of Dr Donald Pinkel (1926–2022) pioneer of curative chemotherapy for children with leukaemia (Supplementary Information and Supplementary Fig. 2). The authors are grateful for funding received from the Wood family—in memory of Artemis. We gratefully acknowledge the FAZA images courtesy of D Vriens, Section of Nuclear Medicine, Department of Radiology, Leiden University Medical Centre (LUMC), Leiden, the Netherlands and Holland Proton Therapy Centre (HollandPTC), Delft, the Netherlands and the bone marrow images with microvessels courtesy of S. E. Sallan, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, USA. We also thank A. Moorman for kindly providing Supplementary Fig. 1 (previously unpublished data). We are grateful to J. Vormoor, A. Roy, T. Graham and A. Borkhardt for helpful comments.

Author information

Authors and Affiliations

  1. Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

    Marcela Braga Mansur & Mel Greaves

  2. Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK

    Nandita M. deSouza

  3. Department of Imaging, The Royal Marsden National Health Service (NHS) Foundation Trust, London, UK

    Nandita M. deSouza

  4. The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer, The Institute of Cancer Research, London, UK

    Rachael Natrajan

  5. Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Lisa M. Abegglen & Joshua D. Schiffman

  6. Peel Therapeutics, Inc., Salt Lake City, UT, USA

    Joshua D. Schiffman

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  1. Marcela Braga Mansur
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  2. Nandita M. deSouza
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  3. Rachael Natrajan
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  4. Lisa M. Abegglen
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  5. Joshua D. Schiffman
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  6. Mel Greaves
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Correspondence to Mel Greaves.

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Nature Ecology & Evolution thanks Subhayan Chattopadhyay, Wei Gu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1 and 2, Text/Information on childhood ALL curability and on TP53, self-renewal and the cure of APML, Table 1 and References.

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Mansur, M.B., deSouza, N.M., Natrajan, R. et al. Evolutionary determinants of curability in cancer. Nat Ecol Evol 7, 1761–1770 (2023). https://doi.org/10.1038/s41559-023-02159-w

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