Login to Access Video or Poster Abstract: MP83-09
Sources of Funding: This work is supported in part by grants NIH/NCI CA140468, CA168601, CA179970, DOD PC130062, and US Department of Veterans Affairs, ORD VA Merits I01BX0002653.

Introduction

Castration resistant prostate cancer (CRPC) is an incurable disease with few durable treatment options. Understanding the mechanisms of disease resistance will allow for the creation of more efficacious therapeutic options. Cabazitaxel is a next-generation taxane drug which is approved for the treatment of CRPC post docetaxel. However, cabazitaxel leads only to a modest survival benefit underlying the need to better understand the mechanisms of resistance to this drug. Whether there exists cross-resistance between docetaxel and cabazitaxel in the CRPC setting is unknown. Here we sought to investigate whether docetaxel resistance leads to the development of cabazitaxel resistance and how this effect may be mediated. _x000D_ _x000D_

Methods

TaxR and DTXR docetaxel-resistant cell line derivatives were created by chronically exposing C4-2B and DU145 cells respectively to increasing doses of docetaxel. Cell growth assays utilizing a coulter cell counter to attain cell numbers were used to assess cellular response to treatment. Colony formation assays were used to support cell growth assay data. Apoptosis was assessed using western blots for cleaved-PARP. TaxR cells stably expressing a plasmid containing a shRNA targeting ABCB1 were used to test the role of ABCB1 in mediating resistance to cabazitaxel.

Results

Cell growth and colony formation assays demonstrated that docetaxel resistant prostate cancer cells are cross-resistant to cabazitaxel. We further show that apoptosis is blunted in docetaxel resistant cells in response to cabazitaxel treatment. Interestingly, both resistant cell lines were completely resistant to high dose docetaxel. 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. Using either a shRNA to decrease the expression of ABCB1 or elacridar, a small molecule inhibitor of ABCB1, re-sensitizes these cells to cabazitaxel treatment and restores the cell death response. We additionally show that inhibition of ABCB1 function using the anti-androgen drugs bicalutamide and enzalutamide effectively re-sensitizes cells to cabazitaxel treatment.

Conclusions

Our work suggests that docetaxel and cabazitaxel resistance is mediated by similar mechanisms. Evidence from other groups demonstrates that cabazitaxel is a better drug in the pre-docetaxel setting. This in conjunction with our work indicates that it may be more beneficial to move cabazitaxel into the docetaxel treatment space. Our study also highlights the potential of combination therapies with anti-androgen drugs to enhance cabazitaxel effectiveness in the docetaxel resistant setting.

Funding

This work is supported in part by grants NIH/NCI CA140468, CA168601, CA179970, DOD PC130062, and US Department of Veterans Affairs, ORD VA Merits I01BX0002653.