Unique targeting of androgen-dependent and -independent AR signaling in prostate cancer to overcome androgen resistance.

Abstract

The androgen receptor (AR) is a major driver of prostate cancer (PCa) and a key therapeutic target for AR inhibitors (ie, Enzalutamide). However, Enzalutamide only inhibits androgen-dependent AR signaling, enabling intrinsic AR activation via androgen-independent pathways, leading to aggressive castration-resistant PCa (CRPC). We investigated the ability of novel anti-cancer agents, Dp44mT and DpC, to overcome androgen resistance. The effect of Dp44mT and DpC on androgen-dependent and independent AR signaling was assessed in androgen-dependent and -independent PCa cells using 2D- and 3D-tissue culture. The clinically trialed DpC was then examined in vivo and compared to Enzalutamide. These agents uniquely promote AR proteasomal degradation and inhibit AR transcription in PCa cells via the upregulation of c-Jun, potently reducing the AR target, prostate-specific antigen (PSA). These agents also inhibited the activation of key molecules in both androgen-dependent and independent AR signaling (ie, EGFR, MAPK, PI3K), which promote CRPC. The clinically trialed DpC also significantly inhibited PCa tumor growth, AR, and PSA expression in vivo, being more potent than Enzalutamide. DpC is a promising candidate for a unique, structurally distinct generation of AR inhibitors that simultaneously target both androgen-dependent and independent arms of AR signaling. No other therapies exhibit such comprehensive and potent AR suppression, which is critical for overcoming the development of androgen resistance.

• Authors: Syer C Lim, Patric J Jansson, Stephen J Assinder, Sanaz Maleki, Des R Richardson, Zaklina Kovacevic
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 9 Pg. 11511-11528 (09 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32713076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• Androgens
• Antineoplastic Agents
• Benzamides
• Nitriles
• Receptors, Androgen
• Thiosemicarbazones
• di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
• Phenylthiohydantoin
• enzalutamide

Topics

• Androgens (metabolism, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Hormone-Dependent (drug therapy, genetics, metabolism)
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Signal Transduction (drug effects)
• Thiosemicarbazones (pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays (methods)