Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res Commun. 2023 Sep 19;3(9):1888-1898. doi: 10.1158/2767-9764.CRC-23-0235.
Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb to the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation of aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) and those treated with leuprolide plus abiraterone (post-Abi) harbor a reservoir of DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 to cause a resurgence of prostate cancer cell growth. We demonstrate that concentrations of DHEA-S found in castrate and post-Abi patients are (i) converted to T in an AKR1C3-dependent manner in prostate cancer cells, and (ii) in amounts sufficient to stimulate AKR1C3-dependent cell growth. We observed this in primary and metastatic prostate cancer cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made by stable isotope dilution LC-MS/MS. We demonstrate AKR1C3 dependence using stable short hairpin RNA knockdown and pharmacologic inhibitors. We also demonstrate that free DHEA is reduced to 5-androstene-3β,17β-diol (5-Adiol) by AKR1C3 and that this is a major metabolite, suggesting that in our cell lines 5-Adiol is a predominant precursor of T. We have identified a mechanism of ARSI resistance common to both primary and metastatic cell lines that is dependent on the conversion of DHEA to 5-Adiol on route to T catalyzed by AKR1C3.
We show that reservoirs of DHEA-S that remain after ARSI treatment are converted into T in primary and metastatic prostate cancer cells in amounts sufficient to stimulate cell growth. Pharmacologic and genetic approaches demonstrate that AKR1C3 is required for these effects. Furthermore, the route to T proceeds through 5-Adiol. We propose that this is a mechanism of ARSI drug resistance.
雄激素受体信号抑制剂 (ARSI) 用于治疗去势抵抗性前列腺癌 (CRPC)，以阻止雄激素受体 (AR) 信号的重新激活。尽管早期取得了成功，但接受 ARSI 治疗的患者最终仍会复发、产生耐药性并死于该疾病。耐药性可能是通过醛酮还原酶家族 1C 成员 3 (AKR1C3) 介导的肿瘤内类固醇生成而发生的。接受亮丙瑞林（去势）治疗的患者和接受亮丙瑞林加阿比特龙（后 Abi）治疗的患者都存在 DHEA-S 储备，这可能通过 AKR1C3 为睾酮 (T) 生物合成提供燃料，从而导致前列腺癌细胞生长的重新激活。我们证明，在去势和后 Abi 患者中发现的 DHEA-S 浓度 (i) 以 AKR1C3 依赖的方式在前列腺癌细胞中转化为 T，并且 (ii) 以足以刺激 AKR1C3 依赖的细胞生长的量存在。我们分别在原发性和转移性前列腺癌细胞系 CWR22PC 和 DuCaP 中观察到了这一点。雄激素测量通过稳定同位素稀释 LC-MS/MS 进行。我们使用稳定的短发夹 RNA 敲低和药理学抑制剂来证明 AKR1C3 的依赖性。我们还证明 AKR1C3 将游离 DHEA 还原为 5-雄烯二酮-3β,17β-二醇 (5-Adiol)，这是一种主要代谢物，表明在我们的细胞系中，5-Adiol 是 T 的主要前体。我们已经确定了一种在原发性和转移性细胞系中都存在的 ARSI 耐药机制，该机制依赖于 AKR1C3 催化的 DHEA 向 T 的转化。
我们表明，在接受 ARSI 治疗后仍然存在的 DHEA-S 储备在原发性和转移性前列腺癌细胞中转化为足以刺激细胞生长的 T。药理学和遗传学方法表明，AKR1C3 是这些作用所必需的。此外，T 的途径是通过 5-Adiol 进行的。我们提出这是 ARSI 药物耐药的一种机制。
