Activation of the ABCB1 Amplicon in Docetaxel- and Cabazitaxel-Resistant Prostate Cancer Cells

Docetaxel and cabazitaxel-based taxane chemotherapy are critical components in the management of advanced prostate cancer. However, their efficacy is hindered due to de novo presentation with or the development of resistance. Characterizing models of taxaneresistant prostate cancer will lead to creation of strategies to overcome insensitivity. We have previously characterized docetaxel-resistant C4-2B and DU145 cell line derivatives, TaxR and DU145-DTXR, respectively. In the present study, we characterize cabazitaxel-resistant derivative cell lines created from chronic cabazitaxel exposure of TaxR and DU145-DTXR cells, CabR and CTXR, respectively. We show that CabR and CTXR cells are robustly resistant to both taxanes but retain sensitivity to antiandrogens. Both CabR and CTXR cells possess increased expression of ABCB1, which is shown to mediate resistance to treatment. Interestingly, we also present evidence for coordinated overexpression of additional genes present within the 7q21.12 gene locus where ABCB1 resides. This locus, known as the ABCB1 amplicon, has been demonstrated to be amplified in multidrug-resistant tumor cells, but little is known regarding its role in prostate cancer. We show that two ABCB1-amplicon genes other than ABCB1, RUNDC3B and DBF4, promote cellular viability and treatment resistance in taxane-resistant prostate cancer models. We present evidence that coordinated amplification of ABCB1-amplicon genes is common in a subset of prostate cancer patients. These data together suggest that ABCB1-amplicon activation plays a critical role in taxane resistance.