Screening a living biobank identifies cabazitaxel as a strategy to combat acquired taxol resistance in high-grade serous ovarian cancer

The anti-mitotic agent taxol (paclitaxel) remains a cornerstone of ovarian cancer treatment. To tackle drug resistance and toxicity, second-generation targeted anti-mitotic agents and combination strategies are being explored but have yet to demonstrate meaningful clinical benefit. A limitation is the lack of a platform to compare strategies in models that capture disease heterogeneity. To overcome this, we screen 83 patient-derived ex vivo ovarian cancer models that exhibit extensive intra- and inter-patient heterogeneity, testing four distinct approaches to enhance taxol sensitivity. Inhibitors of the HSET kinesin or the Mps1 spindle assembly check point kinase show minimal impact on the taxol-sensitivity landscape. By contrast, Bcl-xL inhibition exerts a global anti-proliferative effect. Inhibition of the MDR1 drug-efflux pump restores taxol sensitivity in models characterized by ABCB1 overexpression. These MDR1-driven resistant models also respond to cabazitaxel, which is a poor MDR1 substrate, highlighting a potential therapeutic option for ovarian cancers with acquired taxol resistance.