1. TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer.
- Author
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Lee, Geun Taek, Rosenfeld, Jeffrey A., Kim, Won Tae, Kwon, Young Suk, Palapattu, Ganesh, Mehra, Rohit, Kim, Wun-Jae, and Kim, Isaac Yi
- Subjects
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PROSTATE cancer , *CASTRATION-resistant prostate cancer , *SMALL molecules , *RNA sequencing , *TRANSCRIPTION factors - 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 Transcription Factor-4 (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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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