In a new study published in the British Journal of Cancer, a phenotypic screening was carried out in two prostate cancer cell models to discover novel inhibitors of chemoresistance. The anti-hypertensive drug nicardipine emerged as a potent inhibitor of chemoresistant prostate cancer cells. Nicardipine was shown to be a putative inhibitor of EDD, a subunit of Polycomb repressive complex 2 (PRC2). Coherently with this prediction, nicardipine destabilized another subunit of PRC2, EZH2, leading to an impairment of noncanonical EED–EZH2 signalling. Moreover, nicardipine enhanced the efficacy of docetaxel in xenograft models. Nicardipine is an approved drug with good safety and pharmacological properties. Thus, results from this study provide a good rationale to design biomarker-based trials to assess the efficacy of nicardipine in selected patients with prostate cancer.