Storck William K, May Allison M, Westbrook Thomas C, Duan Zhi, Morrissey Colm, Yates Joel A, Alumkal Joshi J
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States.
Front Endocrinol (Lausanne). 2022 Jul 14;13:926585. doi: 10.3389/fendo.2022.926585. eCollection 2022.
The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events-including chromatin modifications and DNA methylation-play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.
雄激素受体（AR）信号通路对前列腺癌细胞的生长和分化至关重要。因此，药物或手术去势的雄激素剥夺疗法是转移性前列腺癌的主要治疗方法。最近，新型强效AR信号抑制剂（ARSIs）已被开发出来。这些药物可提高转移性去势抵抗性前列腺癌（CRPC）患者的生存率，CRPC是该疾病的致死形式。然而，ARSIs耐药几乎普遍存在。一种最近认识到的耐药机制是谱系可塑性，即从AR驱动的管腔分化程序转变为另一种分化程序。重要的是，在新型ARSIs时代，谱系可塑性的发生率似乎在增加，这强烈表明AR抑制参与了这一过程。谱系可塑性以及从AR驱动的肿瘤转变是一个连续过程，范围从AR活性低的AR表达肿瘤到AR缺失的肿瘤，后者激活了与AR驱动肿瘤中典型管腔程序不同的另一种分化程序。在许多情况下，AR缺失与神经元程序的激活同时发生，最常见的例子是治疗诱导的神经内分泌前列腺癌（t-NEPC）。虽然遗传事件显然有助于前列腺癌谱系可塑性，但表观遗传事件——包括染色质修饰和DNA甲基化——也起着主要作用。现在许多表观遗传因子都可以用药物靶向，这凸显了明确促进谱系可塑性的关键表观遗传因子的重要性。此外，表观遗传标记易于测量，这表明明确哪些测量有助于识别已经经历或有经历谱系可塑性风险的肿瘤很重要。在这篇综述中，我们讨论了AR通路缺失和神经元分化程序激活作为t-NEPC谱系可塑性关键促成因素的作用。我们还讨论了逆转谱系可塑性的新表观遗传治疗策略，包括那些最近已进入临床试验的策略。
