Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment

Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR s...

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Vydáno v:Neoplasia (New York, N.Y.) Ročník 22; číslo 2; s. 111 - 119
Hlavní autoři: Kregel, Steven, Wang, Chao, Han, Xin, Xiao, Lanbo, Fernandez-Salas, Ester, Bawa, Pushpinder, McCollum, Brooke L., Wilder-Romans, Kari, Apel, Ingrid J., Cao, Xuhong, Speers, Corey, Wang, Shaomeng, Chinnaiyan, Arul M.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 01.02.2020
Neoplasia Press
Elsevier
Témata:
Androgen Receptor Antagonists - pharmacology
Androgens - genetics
Androgens - metabolism
Animals
Benzamides - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Resistance, Neoplasm - genetics
Gene Expression Regulation, Neoplastic - drug effects
Humans
Male
Mice
Nitriles - pharmacology
Original article
Phenylthiohydantoin - pharmacology
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
Receptors, Androgen - drug effects
Receptors, Androgen - genetics
Xenograft Model Antitumor Assays
ISSN:1476-5586, 1522-8002, 1476-5586
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Shrnutí:Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.
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These authors contributed equally to the work.
Present address: National Pharmaceutical Teaching Laboratory Center, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Present address: Bristol-Myers Squibb, Redwood City, CA, USA.
Co-senior authors.
ISSN:1476-5586
1522-8002
1476-5586
DOI:10.1016/j.neo.2019.12.003