Data from Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor
Remi Adelaiye‐OgalaBerkley E. GryderYen Thi Minh NguyenAian Neil AlilinAdlai R. GraysonWardah BajwaKeith H. JanssonMichael L. BeshiriSupreet AgarwalJose Antonio Rodriguez-NievesBrian J. CapaldoKathleen KellyDavid J. VanderWeele
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<div>Abstract<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 (<i>NR3C1</i>) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple <i>in vivo</i> 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.</p></div>Keywords:
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<p>PDF file - 133K, Expression levels of members of the NF-kB family in LN-neo and LN-p52 cells.</p>
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<p>PDF file - 118K, Expression levels of anti-apoptotic proteins in LNCaP cells expressing p52 compared to control cells.</p>
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<p>Supplementary Figure S23 provides AR region copy number profiles for all 20 patients that showed a change in the structure of androgen receptor (AR) amplifications after treatment with abiraterone/enzalutamide</p>
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Abstract Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and ARv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. Mol Cancer Ther; 16(12); 2770–9. ©2017 AACR.
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Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.
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<p>Supplementary Figure S23 provides AR region copy number profiles for all 20 patients that showed a change in the structure of androgen receptor (AR) amplifications after treatment with abiraterone/enzalutamide</p>
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<div>Abstract<p>Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and AR<sup>v567es</sup> have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment <i>in vivo</i> in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. <i>Mol Cancer Ther; 16(12); 2770–9. ©2017 AACR</i>.</p></div>
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<div>Abstract<p>Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and AR<sup>v567es</sup> have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment <i>in vivo</i> in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. <i>Mol Cancer Ther; 16(12); 2770–9. ©2017 AACR</i>.</p></div>
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<p>PDF file - 118K, Expression levels of anti-apoptotic proteins in LNCaP cells expressing p52 compared to control cells.</p>
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e16538 Background: One emergent resistance mechanism to medical castration is intratumoral androgen synthesis that activates the androgen receptor (AR). This insight led to the development of the AR antagonist enzalutamide. One enzalutamide resistance mechanism is AR F876L mutations that lead to enzalutamide agonism in some cases. However, mechanisms that contribute to the agonist switch have not been fully clarified, and there are no therapies to block AR F876L. Methods: We usedenzalutamide-resistant cell lines harboring AR F876L mutations to determine mechanisms that contribute to enzalutamide activation of mutant F876L AR. Results: Using these cell line models, we determined that cellular androgen content influences enzalutamide agonism of mutant F876L AR. Further, enzalutamide treatment of AR F876L expressing cell lines recapitulated the effects of androgen activation of F876L AR or wild-type AR. Because the BET bromodomain inhibitor JQ1 was previously shown to block androgen activation of wild-type AR, we tested JQ1 in AR F876L-expressing CRPC models. We determined that JQ1 suppressed androgen or enzalutamide activation of mutant F876L AR and suppressed growth of mutant F876L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. Conclusions: Our data demonstrate that androgens interfere with enzalutamide-induced agonism of F876L mutant AR. Because androgens persist in enzalutamide-resistant CRPC, AR activation by androgens, rather than enzalutamide, may explain why enzalutamide discontinuation does not lead to anti-androgen withdrawal effects clinically. Further, our results provide a cautionary note on therapeutic efforts to deplete androgens concomitantly with enzalutamide treatment as this may accentuate AR agonism by enzalutamide in tumors harboring AR F876L mutations. Finally, targeting BET bromodomain proteins is a promising strategy to suppress mutant AR F876L function irrespective of whether the AR agonist is androgens or enzalutamide.
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