ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer

Abstract

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations which overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small molecule inhibitor elacridar re-sensitizes taxane resistant cells to treatment. Additionally, the anti-androgens bicalutamide and enzalutamide, previously demonstrated to be able to re-sensitize taxane resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to re-sensitize resistant cells to cabazitaxel treatment. Lastly, we show that re-sensitization using an anti-androgen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in utilizing combinations of anti-androgens with cabazitaxel for increased effect in treating advanced CRPC.

Analysis of cabazitaxel‐resistant mechanism in human castration‐resistant prostate cancer

“…In this study, we describe the gene expression profiles and cell cycle patterns of a CBZ‐resistant cell line originally established in our laboratory and identify enhanced ERK signaling as a therapeutic target for CBZ‐resistant CRPC. A previous report described cross‐resistance to CBZ of DOC‐resistant CRPC cell lines . On this point, we also reported the sensitivity of a DOC‐resistant cell line, C4‐2AT6, to CBZ .…”

“…A previous report described cross-resistance to CBZ of DOC-resistant CRPC cell lines. 10 The ERK pathway is evolutionarily conversed and regulates cell proliferation, growth, apoptosis, and differentiation. Enhancement of ERK signaling has been reported to be a risk factor for various cancers such as pancreas, lung, or colorectal carcinomas.…”

Metastatic prostate cancer remains incurable, why?

“…P-gp itself has gained interest as a potential therapeutic target [149] . Preclinical data suggest that ABCB1 expression might play a key role in cross resistance of cabazitaxel after docetaxel and inhibition of ABCB1 resensitizes cell lines to cabazitaxel [150] .…”

“…The potential mechanism is that the taxanes inhibit tubulin-dependent AR nuclear translocation [180] . A recent preclinical study used docetaxel-resistant cell lines to test response to cabazitaxel [150] . They found that docetaxel resistance conferred cross-resistance to cabazitaxel via increased expression of ABCB1, a drug efflux pump.…”

Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy

“…Cabazitaxel is highly cytotoxic with a low affinity for P-gp [ 19 ], and therefore, it is not considered to be clinically cross-resistant with docetaxel, thereby providing a survival benefit for docetaxel-pretreated patients [ 20 ]. However, a recent report indicated that P-gp could mediate cabazitaxel–docetaxel cross-resistance in advanced prostate cancer [ 21 ]. Alternative mechanisms of resistance to taxanes may involve tubulin mutations [ 22 ], although the precise association has yet to be elucidated.…”