Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer

Abstract

Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired b-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy. Cancer Res; 71(18); 6019-29. Ó2011 AACR.

Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

“…[1][2][3][4] These drugs bind b-tubulin and stabilize cellular microtubules, leading to inhibition of microtubule-dependent intracellular trafficking and signaling, mitotic arrest, and apoptotic cell death. [5][6][7] Although taxanes are generally considered antimitotic agents, they also inhibit tumor growth via several different mechanisms. 5 Prostate cancer cells rely heavily on sustained androgen receptor (AR) nuclear signaling, which drives progression despite androgen-deprivation therapy.…”

“…9 Taxanes can therefore inhibit AR nuclear trafficking via stabilization of microtubules; taxaneinduced microtubule stabilization (termed drug-target engagement [DTE]) results in microtubule bundling (MTB), cytoplasmic sequestration of AR, inhibition of AR transcriptional activity, and inhibition of prostate cancer cell growth. 6,7 In summary, the effectiveness of taxanes in prostate cancer can, at least in part, be attributed to the inhibition of AR signaling. 9 Overcoming primary (intrinsic) and secondary (acquired) resistance to taxane therapy remains a challenge in prostate cancer treatment, and several different mechanisms of taxane resistance have been proposed (many of which may operate simultaneously).…”

Prognostic factors in Chinese patients with metastatic castration-resistant prostate cancer treated with docetaxel-based chemotherapy

“…[7][8][9][10][11][12][13][14] However, the magnitude of the benefit provided by each factor has varied among studies, and the value of these factors in predicting overall survival (OS) for Chinese patients is still unclear. In the present study, we retrospectively analysed the data from 115 mCRPC patients treated with docetaxel to explore the prognostic factors of survival outcomes in Chinese patients.…”

Treatment of metastatic prostate cancer

“…The observation that mutations that may explain taxane resistance affect AR nuclear translocation provides a rationale to combine docetaxel with enzalutamide, which prevents AR translocation and also coactivator recruitment. 19 …”