Cancer Metastasis and Tumour Microenvironment Program, Department of Pathology, University of Sydney, Camperdown, NSW, Australia.
Molecular Pharmacology and Pathology Program, Department of Pathology, University of Sydney, Camperdown, NSW, Australia.
FASEB J. 2020 Sep;34(9):11511-11528. doi: 10.1096/fj.201903167R. Epub 2020 Jul 26.
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.
雄激素受体 (AR) 是前列腺癌 (PCa) 的主要驱动因素，也是 AR 抑制剂 (如恩扎卢胺) 的关键治疗靶点。然而，恩扎卢胺仅抑制雄激素依赖性 AR 信号，通过雄激素非依赖性途径使内在 AR 激活，导致侵袭性去势抵抗性 PCa (CRPC)。我们研究了新型抗癌药物 Dp44mT 和 DpC 克服雄激素耐药的能力。使用 2D 和 3D 组织培养，在雄激素依赖性和非依赖性 PCa 细胞中评估了 Dp44mT 和 DpC 对雄激素依赖性和非依赖性 AR 信号的影响。然后在体内检查了经过临床试验的 DpC，并将其与恩扎卢胺进行了比较。这些药物通过上调 c-Jun 独特地促进 AR 蛋白体降解并抑制 PCa 细胞中的 AR 转录，强烈降低 AR 靶标前列腺特异性抗原 (PSA)。这些药物还抑制了在雄激素依赖性和非依赖性 AR 信号中起关键作用的分子的激活（即 EGFR、MAPK、PI3K），从而促进 CRPC。经过临床试验的 DpC 也显著抑制了体内 PCa 肿瘤生长、AR 和 PSA 的表达，其效果强于恩扎卢胺。DpC 是一种很有前途的候选药物，属于一种独特的、结构不同的 AR 抑制剂一代，可同时靶向 AR 信号的雄激素依赖性和非依赖性臂。没有其他疗法表现出如此全面和有效的 AR 抑制作用，这对于克服雄激素耐药性的发展至关重要。
