FOXJ1 mediates taxane resistance through regulation of microtubule dynamics

TL;DR

The paper shows that FOXJ1 helps prostate cancer cells resist docetaxel chemotherapy by altering microtubule behavior, suggesting a new way to identify patients unlikely to benefit from taxane treatment.

Contribution

The study identifies FOXJ1 as a novel regulator of taxane resistance through microtubule dynamics in prostate cancer.

Findings

FOXJ1 overexpression reduces docetaxel-induced microtubule bundling and increases resistance in prostate cancer models.

FOXJ1 gene amplification is linked to poorer survival in taxane-treated prostate cancer patients.

FOXJ1-regulated genes like TPPP3 also contribute to taxane resistance through microtubule regulation.

Abstract

Docetaxel is the first-line chemotherapy for metastatic prostate cancer (PC), but clinically meaningful mechanisms of resistance remain to be established. Here we show, in an in vivo model of docetaxel resistant PC patient-derived xenografts, increased expression of genes that drive development of multiciliated cells including FOXJ1 and its effectors, many of which regulate microtubules (MTs). Mechanistically, FOXJ1 overexpression confers docetaxel resistance in vitro and in vivo, which is associated with decreased docetaxel-mediated MT bundling. Overexpression of a MT-associated FOXJ1-regulated gene (TPPP3) has similar effects. Conversely, FOXJ1 knockdown impairs basal MT function, enhances taxane binding to MTs, and increases docetaxel sensitivity. These results establish mechanistic causality between the FOXJ1 signaling axis, MT biology, and taxane resistance. Clinically, FOXJ1 gene amplification is increased in taxane-treated PC patients. Moreover, in the CHAARTED clinical trial of docetaxel combined with androgen deprivation for metastatic PC, higher baseline FOXJ1 is 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 who will not benefit from taxane treatment.

Taxanes, such as docetaxel or cabazitaxel, are one of the few chemotherapy options for metastatic castration-resistant prostate cancer (mCRPC). Here, the authors discover that FOXJ1 modulation of microtubule dynamics regulates resistance to docetaxel in mCRPC.

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