Abstract 3081: The multiciliated transcription factor FOXJ1 modulates microtubule dynamics and mediates taxane resistance in prostate cancer

Abstract Docetaxel is the first-line chemotherapy for metastatic castration-resistant prostate cancer, 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. Mechanistically, FOXJ1 overexpression conferred docetaxel resistance in vitro and in vivo, which was associated with decreased docetaxel-mediated microtubule bundling. Overexpression of a microtubule-associated FOXJ1-regulated gene (TPPP3) had similar effects. Conversely, FOXJ1 knockdown impaired basal microtubule function, enhanced taxane binding to microtubules, and increased docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, microtubule biology, and taxane resistance. Clinically, FOXJ1 gene amplification was increased in taxane-treated prostate cancer patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic prostate cancer, higher baseline FOXJ1 was predictive of decreased survival in prostate cancer 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. Citation Format: Ada Gjyrezi, Fang Xie, Daniel E. Fein, Maryam Labaf, Larysa Poluben, Olga Voznesensky, Aniket Gad, Eva Corey, Rupal S. Bhatt, Steven Balk, Paraskevi Giannakakou. The multiciliated transcription factor FOXJ1 modulates microtubule dynamics and mediates taxane resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3081.