The androgen receptor (AR) is a critical driver of therapeutic response in patients with metastatic castration- resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and AR-targeting, particularly in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in mCRPC patients. However, therapeutic resistance invariably develops, leading to mortality. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes. Our work and others' established that AR nuclear localization is inhibited by docetaxel (1st line taxane chemotherapy) in androgen-sensitive prostate tumors. In contrast, CRPCs express AR splice variants that remain capable of nuclear trafficking, contributing to taxane resistance. Signaling interactions between androgens/AR and transforming growth factor-β (TGF-β) determine prostate tumor growth and invasion by regulating apoptosis and epithelial-mesenchymal transition (EMT). We recently found that cabazitaxel (2nd line taxane chemotherapy) can reverse EMT, resulting in a mesenchymal-epithelial transition (MET) and kinesin-mediated multi-nucleation, without affecting nuclear AR in in vitro and in vivo prostate cancer models. This work provided the first evidence that cabazitaxel induces phenotypic changes leading to prostate tumor re-differentiation (in addition to apoptosis) dictated by androgens and TGF-β. Here, we hypothesize that treatment with cabazitaxel causes apoptosis in some prostate tumor cells but also diversifies surviving cells into a re-differentiated state (via MET) that confers therapeutic resistance while retaining AR and kinesin activity. We will test this hypothesis by assessing if MET-mediated phenotypic reprogramming of prostate cancer epithelial cells drives therapeutic resistance to taxane chemotherapy/ADT combinations, and if this resistance can be overcome by TGF-β blockade. Three Specific Aims will be addressed: Specific Aim 1 will delineate the role of AR cross-talk with TGF-β in programming prostate tumor MET in response to cabazitaxel in models of CRPC. Specific Aim 2 will determine the mechanisms via which prostate tumor cells undergo taxane-mediated re-differentiation to overcome therapeutic resistance in pre-clinical models of advanced prostate cancer. Specific Aim 3 will test the effect of inhibition of kinesins and centrosome clustering on microtubule-facilitated AR degradation, to sensitize prostate tumors to cabazitaxel. The proposed project will provide new insights into the contribution of TGF-β, AR, and kinesins in taxane-mediated phenotypic changes and define treatment sequencing to overcome resistance in recurrent disease.