Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance.
Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance.
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DOI：
10.1016/j.canlet.2021.06.006
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发表时间：
2021-10-10
期刊：
影响因子：
9.7
通讯作者：
Tang DG
中科院分区：
文献类型：
--
作者：
Jamroze A;Chatta G;Tang DG
雄激素受体（Androgen receptor，AR）是一种配体依赖性核转录因子，属于甾体激素受体家族，通过调节上皮细胞分化和抑制细胞增殖在前列腺器官形成中发挥重要作用。虽然在未经治疗的前列腺癌（PCa）中很少发生突变或扩增，但AR信号转导驱动肿瘤生长，因此，旨在抑制AR信号转导的疗法，称为ARSI（AR信号转导抑制剂），已在临床上使用超过70年。不幸的是，ARSI的临床疗效是短暂的，大多数接受治疗的患者会出现去势抵抗性PCa（CRPC）。已经提出了许多去势抵抗的分子机制;然而，CRPC出现的细胞基础仍然不清楚。CRPC发展的一种未被充分认识的细胞机制是在未经治疗的原发性肿瘤中预先存在的AR异质性，即，尽管大多数PCa细胞表达AR（即，AR+），总是有一群PCa细胞不表达/表达低AR（即，AR−/lo）。重要的是，这种AR异质性在ARSI治疗期间变得更加突出，并且在已建立的CRPC中非常突出。在这里，我们提供了一个简洁的总结AR异质性在PCa连续体，并讨论其对PCa治疗反应的影响。虽然AR+ PCa细胞/克隆对ARSIs表现出极高的敏感性，但AR−/lo PCa细胞/克隆在干细胞信号传导途径中非常丰富，对ARSIs表现出从头抗性。最后，我们提供了几种潜在的组合策略，例如，ARSI与干细胞靶向治疗剂，共同靶向AR+和AR−/lo PCa细胞和转移性克隆。
Androgen receptor (AR), a ligand-dependent nuclear transcription factor and a member of steroid hormone receptor family, plays an important role in prostate organogenesis by regulating epithelial differentiation and restricting cell proliferation. Although rarely mutated or amplified in treatment-naïve prostate cancer (PCa), AR signaling drives tumor growth and as a result, therapies that aim to inhibit AR signaling, called ARSIs (AR signaling inhibitors), have been in clinical use for >70 years. Unfortunately, the clinical efficacy of ARSIs is short-lived and the majority of treated patients develop castration-resistant PCa (CRPC). Numerous molecular mechanisms have been proposed for castration resistance; however, the cellular basis for CRPC emergence has remained obscure. One under-appreciated cellular mechanism for CRPC development is the AR heterogeneity that pre-exists in treatment-naive primary tumors, i.e., although most PCa cells express AR (i.e., AR+), there is always a population of PCa cells that express no/low AR (i.e., AR−/lo). Importantly, this AR heterogeneity becomes accentuated during ARSI treatment and highly prominent in established CRPC. Here, we provide a succinct summary of AR heterogeneity across the PCa continuum and discuss its impact on PCa response to treatments. While AR+ PCa cells/clones exhibit exquisite sensitivities to ARSIs, AR−/lo PCa cells/clones, which are greatly enriched in stem cell signaling pathways, display de novo resistance to ARSIs. Finally, we offer several potential combinatorial strategies, e.g., ARSIs with stem cell targeting therapeutics, to co-target both AR+ and AR−/lo PCa cells and metastatic clones.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
DOI：
10.1158/1078-0432.ccr-17-0017
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kohli M;Ho Y;Hillman DW;Van Etten JL;Henzler C;Yang R;Sperger JM;Li Y;Tseng E;Hon T;Clark T;Tan W;Carlson RE;Wang L;Sicotte H;Thai H;Jimenez R;Huang H;Vedell PT;Eckloff BW;Quevedo JF;Pitot HC;Costello BA;Jen J;Wieben ED;Silverstein KAT;Lang JM;Wang L;Dehm SM
通讯作者：
Dehm SM
影响因子：
3.7
作者：
Grindstad T;Andersen S;Al-Saad S;Donnem T;Kiselev Y;Nordahl Melbø-Jørgensen C;Skjefstad K;Busund LT;Bremnes RM;Richardsen E
通讯作者：
Richardsen E
影响因子：
3
作者：
Isikbay M;Otto K;Kregel S;Kach J;Cai Y;Vander Griend DJ;Conzen SD;Szmulewitz RZ
通讯作者：
Szmulewitz RZ
影响因子：
64.5
作者：
Arora VK;Schenkein E;Murali R;Subudhi SK;Wongvipat J;Balbas MD;Shah N;Cai L;Efstathiou E;Logothetis C;Zheng D;Sawyers CL
通讯作者：
Sawyers CL