Cellular rewiring in lethal prostate cancer: the architect of drug resistance


Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K–AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.

Key points

  • Targeting mechanisms involved in the acquisition of drug resistance could result in more effective therapeutic strategies for patients with prostate cancer.

  • Cellular rewiring can be exploited by prostate cancer cells to acquire drug resistance by implementing alternative bypass signalling pathways after therapy exposure, thus enabling continued tumour proliferation and survival.

  • Tumour cell crosstalk with the microenvironment can also result in cellular rewiring processes that eventually lead to drug resistance.

  • Cellular rewiring mechanisms can induce phenotype switching towards a neuroendocrine phenotype and acquisition of stem-like properties.

  • Clinical trials are investigating the combination of standard therapies, such as anti-androgens, with agents targeting cellular rewiring mechanisms.

  • However, introducing these combinations that target cellular rewiring pathways into the prostate cancer armamentarium will require the development of predictive assays to anticipate toxicities and identify the most effective combinations.

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Fig. 1: Timeline of treatments for advanced prostate cancer.
Fig. 2: Therapeutic targeting of cell rewiring mechanisms contributing to acquired drug resistance.
Fig. 3: Cellular plasticity and switching phenotypes associated with acquired drug resistance.


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J.D.-D. is funded by NIH-NCI R01 CA207311. V.R.-B. is funded by NIH-NCI R01 CA237398 and Prostate Cancer Foundation Young Investigator 2018 award. The authors thank E. W. Gerner for his support of the SKCC Prostate Cancer Program and the laboratory of J.D.-D., and the Philadelphia Prostate Cancer Biome Project for its support of the SKCC Prostate Cancer Program.

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M.C.-C., V.R.-B. and J.D.-D. researched data for the article. All authors made substantial contributions to discussions of content, wrote the manuscript, and reviewed and edited the manuscript before submission.

Correspondence to Veronica Rodriguez-Bravo or Josep Domingo-Domenech.

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Carceles-Cordon, M., Kelly, W.K., Gomella, L. et al. Cellular rewiring in lethal prostate cancer: the architect of drug resistance. Nat Rev Urol (2020). https://doi.org/10.1038/s41585-020-0298-8

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