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Androgen-targeted Therapy-Induced Epithelial Mesenchymal Plasticity and Neuroendocrine Transdifferentiation in Prostate Cancer: An Opportunity for Intervention

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Review

Androgen-targeted Therapy-Induced Epithelial Mesenchymal Plasticity and Neuroendocrine Transdifferentiation in Prostate Cancer: An Opportunity for Intervention

Mannan Nouri et al. Front Oncol.

Abstract

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

Keywords: Axl; androgen deprivation therapy; brachyury; castrate resistant; epithelial-to-mesenchymal transition; neuroendocrine; prostate cancer; tumor cell plasticity.

Figures

Figure 1
Figure 1
Inhibition of androgen receptor (AR) signaling using androgen-targeted therapies (ATT) induces adaptive responses including epithelial–mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) in prostate cancer cells. These phenotypes are associated with CRPC (castrate resistance prostate cancer). Inhibition of plasticity drivers Brachyury, Axl, MEK, and Aurora kinase A provide potential mechanisms to reduce the induction of the EMT and/or NEtD phenotypes.

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