Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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 (<jats:italic>NR3C1</jats:italic>) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple <jats:italic>in vivo</jats:italic> models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked anti-tumor 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.</jats:p><jats:sec><jats:title>SIGNIFICANCE</jats:title><jats:p>Induced GR expression is compensatory for AR blockade and confers resistance to AR-targeted therapy. Here we show that inhibition of the PI3K/AKT pathway remodels the chromatin landscape, blocks the induction of GR expression and overrides enzalutamide resistance.</jats:p></jats:sec>

A Mechanistic Modeling Framework Reveals the Key Principles Underlying Tumor Metabolism

“…Further, PI3K / Akt inhibition, which will downregulate de novo fatty acid synthesis, has been shown to deplete the H3K27ac epigenetic modification, thereby remodeling the chromatin landscape. This epigenetic remodeling can hinder the emergence of resistance to androgen receptor inhibition (65). Previous studies have proposed that epigenetic changes in response to metabolic stress induced by environmental changes can increase transcriptional variability in cells.…”

Exosomes in Liquid Biopsy: A Nanotool for Postradiotherapy Cancer Monitoring

“…Activation of the MAPK signaling pathway and the PI3K-AKT axis facilitates prostate cancer growth, migration, and invasion [145,146], while inhibition of this pathway and axis showed the opposite effects [147,148]. Activation of the PI3K-AKT axis is involved in the chemoresistance of prostate cancer [149,150]. Another study identified five differentially expressed miRNAs in the serum exosomes of prostate cancer patients, including hsa-let-7a-5p, hsa-miR-141-3p, hsa-miR-145-5p, hsa-miR-21-5p and hsa-miR-99b-5p [90].…”

Genome-wide crosstalk between steroid receptors in breast and prostate cancers

“…Thus, a more viable option to treat TNBC or GR-induced ENZ-resistant PCa would be to inhibit the action of the GR through other signaling pathways, while retaining the beneficial systemic effect of glucocorticoids. In ENZ-resistant PCa, these kinds of pathways could be BET ( Shah et al 2017 ) or PI3K/AKT ( Adelaiye-Ogala et al 2020 ), whereas in TNBC, STAT3 ( Conway et al 2020 ) or p38 MAPK ( Perez Kerkvliet et al 2020 ) could be targeted. Future investigations will determine if sufficient attenuation of GR signaling can be obtained through these pathways or if other yet to be discovered pathways will be more effective.…”