Unique targeting of androgen-dependent and -independent AR signaling in prostate cancer to overcome androgen resistance
Author(s)
Lim, Syer C
Jansson, Patric J
Assinder, Stephen J
Maleki, Sanaz
Richardson, Des R
Kovacevic, Zaklina
Griffith University Author(s)
Year published
2020
Metadata
Show full item recordAbstract
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 ...
View more >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.
View less >
View more >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.
View less >
Journal Title
FASEB Journal
Volume
34
Issue
9
Subject
Biochemistry and cell biology
Zoology
Medical physiology
Science & Technology
Life Sciences & Biomedicine
Biology
Molecular Biology