We studied mechanisms of resistance to the novel
taxane cabazitaxel in established cellular models of
taxane resistance. We also developed
cabazitaxel-resistant variants from MCF-7
breast cancer cells by stepwise selection in
drug alone (MCF-7/CTAX) or
drug plus the transport inhibitor
PSC-833 (MCF-7/CTAX-P). Among multidrug-resistant (MDR) variants,
cabazitaxel was relatively less cross-resistant than
paclitaxel and
docetaxel (15- vs. 200-fold in MES-SA/Dx5 and 9- vs. 60-fold in MCF-7/TxT50, respectively). MCF-7/TxTP50 cells that were negative for MDR but had 9-fold resistance to
paclitaxel were also 9-fold resistant to
cabazitaxel. Selection with
cabazitaxel alone (MCF-7/CTAX) yielded 33-fold resistance to
cabazitaxel, 52-fold resistance to
paclitaxel, activation of ABCB1, and 3-fold residual resistance to
cabazitaxel with MDR inhibition. The MCF-7/CTAX-P variant did not express ABCB1, nor did it efflux rhodamine-123,
BODIPY-labeled
paclitaxel, and [(3)H]-
docetaxel. These cells are hypersensitive to depolymerizing agents (
vinca alkaloids and
colchicine), have reduced baseline levels of stabilized microtubules, and impaired
tubulin polymerization in response to
taxanes (
cabazitaxel or
docetaxel) relative to MCF-7 parental cells. Class III β-
tubulin (TUBB3)
RNA and
protein were elevated in both MCF-7/CTAX and MCF-7/CTAX-P. Decreased BRCA1 and altered epithelial-mesenchymal transition (EMT) markers are also associated with
cabazitaxel resistance in these MCF-7 variants, and may serve as predictive
biomarkers for its activity in the clinical setting. In summary,
cabazitaxel resistance mechanisms include MDR (although at a lower level than
paclitaxel and
docetaxel), and alterations in microtubule dynamicity, as manifested by higher expression of TUBB3, decreased BRCA1, and by the induction of EMT.