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Treatment resistance in urothelial carcinoma: an evolutionary perspective

Nature Reviews Clinical Oncology volume 15, pages 495–509 (2018)Cite this article

Subjects

Abstract

The emergence of treatment-resistant clones is a critical barrier to cure in patients with urothelial carcinoma. Setting the stage for the evolution of resistance, urothelial carcinoma is characterized by extensive mutational heterogeneity, which is detectable even in patients with early stage disease. Chemotherapy and immunotherapy both act as selective pressures that shape the evolutionary trajectory of urothelial carcinoma throughout the course of the disease. A detailed understanding of the dynamics of evolutionary drivers is required for the rational development of curative therapies. Herein, we describe the molecular basis of the clonal evolution of urothelial carcinomas and the use of genomic approaches to predict treatment responses. We discuss various mechanisms of resistance to chemotherapy with a focus on the mutagenic effects of the DNA dC->dU-editing enzymes APOBEC3 family of proteins. We also review the evolutionary mechanisms underlying resistance to immunotherapy, such as the loss of clonal tumour neoantigens. By dissecting treatment resistance through an evolutionary lens, the field will advance towards true precision medicine for urothelial carcinoma.

Key points

  • The emergence of therapy-resistant clones is a critical barrier to cure in patients with urothelial carcinoma.

  • The bulk of mutations in cancer driver genes accumulate early in the evolution of urothelial carcinoma in a pattern characteristic of DNA dC->dU editing enzyme APOBEC3 (APOBEC3)-mediated mutagenesis.

  • APOBEC3-mediated mutagenesis (stochastically) and cisplatin-based chemotherapy (deterministically) shape the evolutionary trajectory of urothelial carcinoma; early branching evolution is subject to clonal selection of APOBEC3-associated mutations following chemotherapy.

  • A high mutational load translates into neoantigenesis, evoking a robust antitumour immune response and higher sensitivity to immune-checkpoint inhibition.

  • As urothelial carcinomas evolve, they exploit several mechanisms of immune evasion, including neoantigen loss, major histocompatibility complex loss, downregulation of immunostimulatory signals, and activation of inhibitory signals.

  • Evolution-targeted therapeutic strategies, such as adaptive therapy and targeting of temporal collateral sensitivity, should be combined with precise tailoring of chemotherapeutic and immunotherapeutic interventions.

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Fig. 1: The APOBEC3 proteins are evolutionary drivers of urothelial carcinoma.
Fig. 2: A conceptual model of the relationship between APOBEC3-induced mutational load and evolutionary fitness in urothelial carcinoma.
Fig. 3: APOBEC3-induced mutagenesis and chemotherapy shape the evolutionary trajectory of urothelial carcinoma.
Fig. 4: The development of immune evasion in urothelial carcinoma.
Fig. 5: Precision targeting of clonal evolution.

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Acknowledgements

The authors thank S. Maleki Vareki, Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada, for his diligent proofreading of this manuscript.

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  1. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA

    Panagiotis J. Vlachostergios & Bishoy M. Faltas

  2. Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, NY, USA

    Bishoy M. Faltas

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Vlachostergios, P.J., Faltas, B.M. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nat Rev Clin Oncol 15, 495–509 (2018). https://doi.org/10.1038/s41571-018-0026-y

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