Abstract Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Previous work showed dynamic interconversions between epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) defines the phenotypic landscape of prostate tumors, as a potential driver of emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa PDX models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between anti-androgen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential gene signature response to cabazitaxel. Gene pathway analysis showed that sensitive cells exhibit increase in DNA damage, while resistant cells express genes associated with protein regulation in response to cabazitaxel. These PDX specimens are from patients who have metastatic lethal CRPC, treated with androgen-deprivation therapy (ADT), antiandrogens and chemotherapy including 2nd line taxane chemotherapy, cabazitaxel. Immunohistochemistry revealed high expression of E-cadherin and low expression of vimentin resulting in re-differentiation toward an epithelial phenotype. Furthermore, the mitotic kinesin-related protein (HSET) involved in microtubule binding and the SLCO1B3 transporter (implicated in cabazitaxel intracellular transport), associated with resistance in these prostate tumors. Combinational targeting of kinesins (ispinesib) with cabazitaxel was more effective than single monotherapies in inducing cell death in resistant prostate tumors. Implications: Our findings are of translational significance in identifying kinesin as a novel target of cross-resistance, towards enhancing therapeutic vulnerability and improved clinical outcomes in patients with advanced prostate cancer.