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Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer

Nature Reviews Clinical Oncology volume 14, pages 269–283 (2017)Cite this article

Subjects

Key Points

  • Potent androgen receptor (AR)-targeted therapies have increased survival rates for metastatic castration-resistant prostate cancer (mCRPC), but correlate with the emergence of 'treatment-induced lineage crisis' characterized by visceral and bulky metastases and low PSA secretion

  • In prostate cancer, lineage crisis can occur either in the form of treatment-induced neuroendocrine differentiation, which results in a neuroendocrine phenotype, or in the form of treatment-induced epithelial-to-mesenchymal transition

  • Regardless of the mechanism responsible for lineage crisis, a proposed common checkpoint that precedes such crisis is the loss of expression and/or activity of AR pathway (AR-lo prostate cancer)

  • Drug-cycling designs used to prevent multidrug resistance (or 'superbugs') in infectious diseases might delay treatment-induced lineage crisis in prostate cancer, owing to the partial similarities between both phenomena

  • The PRINT protocol is a phase II trial designed to alternate administration of FDA-approved drugs in rapid cycles of 3 months to prevent treatment-induced lineage crisis for mCRPC, which might provide a rationale for testing drug cycling in the setting of first-line treatment for mCRPC

  • Collateral sensitivity might result in increased cytotoxic effects compared with standard approaches for mCRPC (a heterogeneous disease); this treatment strategy uses synergistic drug pairs because drug resistance results in competitive fitness

Abstract

The increasing potency of therapies that target the androgen receptor (AR) signalling axis has correlated with a rise in the proportion of patients with prostate cancer harbouring an adaptive phenotype, termed treatment-induced lineage crisis. This phenotype is characterized by features that include soft-tissue metastasis and/or resistance to standard anticancer therapies. Potent anticancer treatments might force cancer cells to evolve and develop alternative cell lineages that are resistant to primary therapies, a mechanism similar to the generation of multidrug- resistant microorganisms after continued antibiotic use. Herein, we assess the hypothesis that treatment-adapted phenotypes harbour reduced AR expression and/or activity, and acquire compensatory strategies for cell survival. We highlight the striking similarities between castration-resistant prostate cancer and triple-negative breast cancer, another poorly differentiated endocrine malignancy. Alternative treatment paradigms are needed to avoid therapy-induced resistance. Herein, we present a new clinical trial strategy designed to evaluate the potential of rapid drug cycling as an approach to delay the onset of resistance and treatment-induced lineage crisis in patients with metastatic castration-resistant prostate cancer.

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Figure 1: Treatment-induced resistance and evolution to lineage crisis.
Figure 2: Treatment cycling to prevent progression to treatment-induced mCRPC.
Figure 3: Drug cycling with collateral sensitivity.

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Acknowledgements

The authors want to thank M. Galsky, J. Sfakianos, A. Wolfe and M. Ruscetti for constructive advice. This work was supported in part by a grant from the Fondation de France to G.R. and an NIH grant (R01CA197910) to D.J.M.

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Authors and Affiliations

  1. Department of Medical Oncology, Institut Bergonié, 229 Cours de l'Argonne, Bordeaux, 33076, France

    Guilhem Roubaud

  2. Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, 1470 Madison Avenue, New York, 10029, New York, USA

    Bobby C. Liaw, William K. Oh & David J. Mulholland

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  1. Guilhem Roubaud
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Contributions

G.R. and D.J.M researched data and wrote the manuscript. All authors discussed the article's contents, revised and edited the manuscript before submission. B.C.L. and W.K.O. designed the PRINT clinical protocol.

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Correspondence to David J. Mulholland.

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Roubaud, G., Liaw, B., Oh, W. et al. Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer. Nat Rev Clin Oncol 14, 269–283 (2017). https://doi.org/10.1038/nrclinonc.2016.181

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