Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Sci Transl Med. 2021 May 26;13(595). doi: 10.1126/scitranslmed.abe8226.
Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH → 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-derived cell lines, and patient-derived prostate tissues treated ex vivo with enzalutamide. Genetically silencing H6PD blocks NADPH generation, which inhibits the usual reductive directionality of 11β-HSD1, to effectively replace 11β-HSD2 function in human-derived cell line models, suppress the concentration of biologically active glucocorticoids in prostate cancer, and reverse enzalutamide resistance in mouse xenograft models. Similarly, pharmacologic blockade of H6PD with rucaparib normalizes tumor glucocorticoid metabolism in human cell lines and reinstates responsiveness to enzalutamide in mouse xenograft models. Our data show that blockade of H6PD, which is essential for glucocorticoid synthesis in humans, normalizes glucocorticoid metabolism and reverses enzalutamide resistance in mouse xenograft models. We credential H6PD as a pharmacologic vulnerability for treatment of next-generation androgen receptor antagonist-resistant prostate cancer by depleting tumor glucocorticoids.
前列腺癌对恩扎鲁胺的下一代激素治疗产生耐药性是一个主要问题，并最终导致疾病的致命性。刺激糖皮质激素受体（GR）的生物活性糖皮质激素具有 11β-OH 部分，而耐药肿瘤表现出 11β-HSD2 的缺失，该酶是氧化（11β-OH→11-keto）酶，可使糖皮质激素失活，从而使肿瘤糖皮质激素升高，通过刺激 GR 来驱动耐药性。在这里，我们表明，在接受恩扎鲁胺治疗的男性、人源性细胞系和接受恩扎鲁胺离体处理的患者源性前列腺组织中，前列腺癌组织中己糖-6-磷酸脱氢酶（H6PD）蛋白上调。遗传沉默 H6PD 会阻止 NADPH 的产生，从而抑制 11β-HSD1 的通常还原方向性，有效地在人源性细胞系模型中替代 11β-HSD2 功能，抑制前列腺癌中生物活性糖皮质激素的浓度，并逆转小鼠异种移植模型中的恩扎鲁胺耐药性。类似地，用鲁卡帕尼抑制 H6PD 的药理阻断作用可使人类细胞系中的肿瘤糖皮质激素代谢正常化，并恢复对恩扎鲁胺的反应性在小鼠异种移植模型中。我们的数据表明，阻断 H6PD（这是人类糖皮质激素合成所必需的）可使糖皮质激素代谢正常化，并逆转小鼠异种移植模型中的恩扎鲁胺耐药性。我们将 H6PD 鉴定为通过耗尽肿瘤糖皮质激素来治疗下一代雄激素受体拮抗剂耐药性前列腺癌的药理脆弱性。
