FOXJ1 mediates taxane resistance through regulation of microtubule dynamics

Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. We generated an in vivo model of docetaxel resistance using castration-resistant patient-derived xenografts and found increased expression of genes that drive development of multiciliated cells, including FOXJ1 and its effector genes, many of which regulate ciliary microtubules (MTs). Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene ( TPPP3 ) had similar effects. Conversely, FOXJ1 knockdown impaired basal MT function, enhanced taxane binding to MTs, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 was predictive of decreased survival in PC patients treated with docetaxel, further supporting clinical relevance. Together these findings identify a previously unrecognized clinically impactful mechanism of taxane resistance whose exploitation could stratify patients that will not benefit from taxane treatment.