• Targeting the crosstalk between AR3 and E2F1 as a prospective therapy for drug-resistant prostate cancer

      Xu, Jin; Qiu, Yun (2020)
      Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drugs that inhibit the growth of cells that are resistant to standard chemo and androgen deprivation therapy, and determine the underlying mechanisms of their action. To achieve this aim, we established cell lines that are resistant to this standard combination drug treatment and tested new compounds to overcome this “double drug” resistance. Results: Our results show that combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either DTX or ENZ alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. Specifically, E2F1 regulates AR3 and forms a positive regulatory feed-forward loop. Moreover, this drug combination treatment also results in DNA double strand break via the E2F1-AR3 signaling axis. Importantly, we established new drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these double drug-resistant cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame the drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer.