Drug Resistance Mediated by Gene Expression in Prostate Cancer

Patients with castration-resistant prostate cancer (CRPC) who are resistant to docetaxel and Jevtana (cabazitaxel) may be resistant because of the overexpression of the ABCB1 gene, according to results of an investigation presented at the 2017 American Urological Association Annual Meeting. Inhibiting this gene with antiandrogen therapy — such as Xtandi (enzalutamide) and Casodex (bicalutamide) – may be the answer to increasing efficiency of tanxane-based therapies.

Docetaxel has long been the standard first-line treatment for patients with CRPC. However, patients can either present with or develop a resistance to taxanes, leaving a large unmet need for treating patients with this resistance. Jevtana is a next-generation taxane that was approved recently to treat patients previously treated with docetaxel. Despite having a benefit in overall survival over other agents in the postdocetaxel setting, patients treated with Jevtana also experience resistance, and ultimately disease progression. Therefore, a deeper understanding of what drives this resistance will help urologists treat these patients.

The ABCB1 gene is a cell membrane efflux pump, and a member of the MDR/TAP subfamily of ATP-binding cassette (ABC) transporters. ABCB1 is responsible for less drug accumulation in multidrug-resistant cells and can mediate resistance to anticancer drugs.

“Our previous work showed that increased expression of ABCB1 was largely responsible for mediating resistance to docetaxel. Thus, we sought to test whether this would alter cellular response to cabazitaxel,” Alan P. Lombard, Ph.D., of the University of California Davis Medical Center, and colleagues wrote in the abstract for the poster.

The investigators performed numerous cell growth and colony formation assays to attain cell numbers to assess cellular responses to Jevtana. They demonstrated that TaxR and DU145-DTXR docetaxel-resistant prostate cancer cells are cross-resistant to Jevtana. Further assays showed that cells resistant to docetaxel are also completely resistant to high-dose docetaxel, but do have some response to high-dose Jevtana.

Additionally, the investigators noted, using either an shRNA or elacridar (a small molecule inhibitor of ABCB1) to decrease the expression of ABCB1 re-sensitizes cells resistant to docetaxel to treatment with Jevtana and restores the cell death response.

When the investigators administered Casodex to the resistant cells, ABCB1 activity was blocked and the cell growth assays showed that these cells were re-sensitized to treatment with Jevtana. Further, the investigators discovered that Casodex could also re-sensitize TaxR and DU145-DTXR cells to Jevtana. Xtandi behaved similarly in re-sensitizing docetaxel-resistant cells to treatment with Jevtana. Notably, the cell growth assays also demonstrated that Xtandi and Casodex could restore Jevtana-induced apoptosis in TaxR and DU145-DTXR cells.

This research provides a better understanding of the mechanism of resistance for a large and underserved population of patients with CRPC. It could even indicate not only that there is potential for combination therapies with antiandrogen agents to enhance the effectiveness of Jevtana in the docetaxel-resistant setting, but also that Jevtana may be a better drug in the pre-docetaxel setting for these patients. “Our work indicates that it may be more beneficial to move Jevtana into the docetaxel treatment space,” Lombard et al concluded.