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bioRxiv · 10.1101/560821

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

lee, G. T.·Kim, W. T.·Kwon, Y. S.·Palapattu, G.·Kim, W.-J.·Kim, I. Y.
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Abstract

In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.

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lee, G. T., Kim, W. T., Kwon, Y. S., Palapattu, G., Kim, W.-J., Kim, I. Y.. 2019-02-25. TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer. https://doi.org/10.1101/560821

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