Research ArticleCancer

Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation

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Science Translational Medicine  26 May 2021:
Vol. 13, Issue 595, eabe8226
DOI: 10.1126/scitranslmed.abe8226

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Restoring tumor metabolism

Androgen receptor antagonists have been shown to be effective in the treatment of prostate cancer. However, patients develop mechanisms of resistance associated with loss of the enzyme that inactivates glucocorticoids. Now, Li et al. investigated the mechanisms mediating the resistance to the androgen receptor antagonist enzalutamide (enz) in cancer tissue from patients and mouse xenograft models. The authors reported that treatment with enz induced an up-regulation of hexose-6-phosphate dehydrogenase (H6PD) in human tumor tissue and cell lines. Genetic or pharmacological blockade of H6PD restored glucocorticoid metabolism and sensitivity to enz in vitro and in vivo, suggesting that H6PD could be targeted to overcome pharmacoresistance in prostate cancer.

Abstract

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.

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