Plk1 inhibition enhances the efficacy of BET epigenetic reader blockade in castration-resistant prostate cancer

Fengyi Mao, Jie Li, Qian Luo, Ruixin Wang, Yifan Kong, Colin Carlock, Zian Liu, Bennet D. Elzey, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the b-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of b-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling.

Original languageEnglish
Pages (from-to)1554-1565
Number of pages12
JournalMolecular Cancer Therapeutics
Issue number7
StatePublished - Jul 2018

Bibliographical note

Funding Information:
We gratefully acknowledge Sandra Torregrosa-Allen and Melanie Currie for their help with animal study. This work was supported by NIH R01 CA157429 (to X. Liu), NIH R01 CA192894 (to X. Liu), NIH R01 CA196835 (to X. Liu), and NIH R01 CA196634 (to X. Liu).

Publisher Copyright:
© 2018 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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