title: 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 [(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.
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: George E
authors.initials: GE
authors.lastname: Duran
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Yan C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: E Brian
authors.initials: EB
authors.lastname: Francisco
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: John C
authors.initials: JC
authors.lastname: Rose
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Stanford Functional Genomics Facility, Stanford University School of Medicine, Stanford, California.
authors.forename: John
authors.initials: J
authors.lastname: Coller
authors.affiliation: Sanofi Oncology, Bridgewater, New Jersey.
authors.forename: Diana
authors.initials: D
authors.lastname: Brassard
authors.affiliation: Sanofi Oncology, Vitry-sur-Seine, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Vrignaud
authors.affiliation: Oncology Division, Department of Medicine, Stanford University School of Medicine, Stanford, California. brandy@stanford.edu.
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D043823:Taxoids / Q000494:pharmacology*; D014404:Tubulin / Q000235:genetics* / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D003524:Cyclosporins; C578986:TUBB1 protein, human; D043823:Taxoids; D014404:Tubulin; C552428:cabazitaxel; C070272:valspodar