Mechanisms of Resistance to Cabazitaxel

Abstract

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 [3H]-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.

Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44

“…P-gpexpressing sublines were derived from the corresponding non-P-gp-expressing parental tumor cell lines by selection with different anticancer drugs (2,9,22). We also observed that triptolide nearly equipotently killed human pancreatic cancer Capan-1 and Ewing sarcoma SK-ES-1 cells and PARP inhibitor simmiparibselected resistant variants Capan-1/SP (RF: 0.84) and SK-ES-1/SP (RF: 1.36), and these variants did not express detectable drug transporters, including P-gp, MRP1, or BRCP (data not shown).…”

“…We evaluated triptolide potency in P-gp-expressing cell variants, including doxorubicin-selected variants, MES-SA/DX5 (22), and K562/A02 (2), and vincristine-selected KB/VCR (9). These sublines were resistant to agents used for their establishment, respectively as depicted in Fig.…”

Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer

“…Interestingly, washing did not impact the intracellular concentration of the drug, unlike Docetaxel-treated MCF-7 cells which demonstrated 50% concentration of drug postwashing, indicating that Cabazitaxel is better retained and thusly efficacious inside cells (Azarenko et al, 2014). Despite this improvement in intracellular retention, MDR-resistant MCF-7 variant cells still demonstrated resistance to the effects of Cabazitaxel although it was lower than that observed for Paclitaxel and Docetaxel (Duran et al, 2014).…”

“…Increased expression of the isotype βIII-tubulin has been clinically demonstrated for lung, breast, and ovarian cancers; in addition, overexpression of the βIII-tubulin isoform has been associated with progression to mCRPC, and is predictive not only of Docetaxel efficacy ( Fig. 3B; Ploussard et al, 2010;Terry et al, 2009), but also of Cabazitaxel to therapeutic resistance (Duran et al, 2014).…”

“…EMT has been implicated in the development, progression, and therapeutic failure in different cancers ( Fig. 3G; Duran et al, 2014;Kalluri & Weinberg, 2009;Yilmaz & Christofori, 2009). …”