Cedars-Sinai Medical Center, Division of Cancer Biology and Therapeutics, Departments of Surgery & Biomedical Sciences; China Medical University, Graduate Institute of Biomedical Sciences
Treatment of prostate cancer (PC) by androgen suppression is associated with the emergence of aggressive variants that exhibit variable dependence on the androgen receptor (AR). Here we identify the developmental transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 suppresses the AR transcriptional program and activates genes associated with neural differentiation and lethal progression. Inhibition of OC2 by a newly identified small molecule suppresses PC metastasis in mice. These findings suggest that OC2 displaces ARdependent growth and survival mechanisms in a substantial subset of mCRPC where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC.
Rotinen, Mirja and You, Sungyong and Yang, Julie and Coetzee, Simon and Huang, Wen-Chin and Huang, Fangjin and Pan, Xinlei and Yáñez, Alberto and Hazelett, Dennis and Chu, Chia-Yi and Chung, Leland and Freedland, Stephen J. and Di Vizio, Dolores and Garraway, Isla P. and Murali, Ramachandran and Knudsen, Beatrice S. and Freeman, Michael, ONECUT2 Is a Targetable Master Regulator of Lethal Prostate Cancer That Suppresses the Androgen Axis (2018). Available at SSRN: https://ssrn.com/abstract=3155552 or http://dx.doi.org/10.2139/ssrn.3155552
This version of the paper has not been formally peer reviewed.
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