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Drug resistance in metastatic castration-resistant prostate cancer

Nature Reviews Clinical Oncology volume 8, pages 12–23 (2011)Cite this article

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Abstract

Docetaxel in combination with prednisone is the standard of care in men with symptomatic castration-resistant prostate cancer (CRPC). However, a substantial proportion of men with CRPC do not benefit from docetaxel or other systemic therapy and those who do benefit invariably progress and die of (or with) prostate cancer. Resistance to chemotherapy in metastatic CRPC is a result of cellular mechanisms of drug resistance intrinsic to prostate cancer and general mechanisms common to different tumor types. Continued signaling from the androgen receptor, activation of oncogenic survival pathways by various receptor tyrosine kinases and crosstalk between the androgen receptor and these oncogenic survival pathways are hallmarks of progression of CRPC. General mechanisms of drug resistance include the existence of subpopulations of cancer cells with cellular mechanisms of resistance, resistance related to interactions between prostate cancer cells and their surrounding microenvironment and impaired drug delivery to the cancer cells. New therapeutics targeting these mechanisms are under evaluation in clinical trials. Drug resistance in metastatic CRPC is multifactorial and complex and development of new medical therapies remains challenging.

Key Points

  • Although the combination of docetaxel and prednisone prolongs survival and improves the quality of life of patients with metastatic castration-resistant prostate cancer (CRPC), the disease invariably progresses

  • Resistance to docetaxel and other types of systemic therapy can develop owing to mechanisms intrinsic to the biology of prostate cancer and/or general mechanisms of drug resistance common to different tumor types

  • Cellular hallmarks of CRPC include continued signaling by the androgen receptor (AR), activation of various pathways associated with proliferation and survival, and crosstalk between the AR and these pathways

  • The existence of subpopulations of cancer cells with cellular mechanisms of resistance, interactions between cancer cells and their surrounding microenvironment, and impaired drug distribution can contribute to drug resistance in prostate cancer

  • New agents that target the critical cellular mechanisms of drug resistance are the most promising in metastatic CRPC; proof-of-principle clinical studies have shown activity for new agents targeting signaling from the AR and cellular mechanisms of resistance to taxanes

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Figure 1: Mechanisms of resistance to docetaxel in metastatic prostate cancer.
Figure 2: Drug resistance due to continued or upregulated signaling from the AR.
Figure 3: Representation of cancer cells and the ECM surrounding a capillary.
Figure 4: Distribution of doxorubicin in the prostate tumor PC3 xenograft.
Figure 5: Cellular mechanisms of resistance to taxanes.

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C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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  1. Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, M5G 2M9, ON, Canada

    Bostjan Seruga, Alberto Ocana & Ian F. Tannock

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Seruga, B., Ocana, A. & Tannock, I. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol 8, 12–23 (2011). https://doi.org/10.1038/nrclinonc.2010.136

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