Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor

Remi Adelaiye-Ogala, Berkley E. Gryder, Yen Thi Minh Nguyen, Aian Neil Alilin, Adlai R. Grayson, Wardah Bajwa, Keith H. Jansson, Michael L. Beshiri, Supreet Agarwal, Jose Antonio Rodriguez-Nieves, Brian Capaldo, Kathleen Kelly, David J. VanderWeele

Research output: Contribution to journalArticle

Abstract

The PI3K-AKT pathway has pleiotropic effects and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following androgen receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple in vivo models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked antitumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state.

Original languageEnglish (US)
Pages (from-to)1436-1447
Number of pages12
JournalMolecular cancer therapeutics
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Adelaiye-Ogala, R., Gryder, B. E., Nguyen, Y. T. M., Alilin, A. N., Grayson, A. R., Bajwa, W., Jansson, K. H., Beshiri, M. L., Agarwal, S., Rodriguez-Nieves, J. A., Capaldo, B., Kelly, K., & VanderWeele, D. J. (2020). Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor. Molecular cancer therapeutics, 19(7), 1436-1447. https://doi.org/10.1158/1535-7163.MCT-19-0936