The emerging role of cross-resistance between taxanes and AR-targeting therapy in metastatic prostate cancer

Background: To date, the number of prostate cancer ranked first among newly diagnosed malignant tumors in men from multiple countries. Localized prostate cancer could be controlled by curative therapy. However, for patients with metastatic prostate cancer (mPC), the prognosis is poor. As among first-line treatments of systemic therapies for mPC, docetaxel and androgen receptor (AR)-targeted therapies have been widely used. However, mPC patients inevitably developed resistance to the current therapy. More importantly, there is a cross-resistance between docetaxel-based chemotherapy and AR-targeting therapy during the treatment process, which could impair the overall survival benefits without proper administration. Objective: Therefore, it is urgent to elucidate the mechanism of cross-resistance and explore the optimal sequential strategy. Methods: Here, in this review, we systematically reviewed and summarised the updated literature on clinical evidence and mechanistic research of treatment resistance in mPC. Results: Emerging evidence indicated that AR splice variants, AR overexpression or mutations, AR nuclear translocation, as well as AR signaling reactivation collectively contributed to the cross-resistance. With the current understanding of cross-resistance, multiple solutions are promising for improving the benefits, including refining the sequencing of available therapies for mPC, in combination with potential targeted inhibitors or immune checkpoint inhibitors. Further studies are needed to explore the combination of emerging strategies and eventually control the progression of prostate cancer. Conclusions: This review defined the mutual and unique resistant mechanism of these treatments, which might help to focus and accelerate therapeutic research that may ultimately improve clinical outcomes for patients with prostate cancer.