TY - JOUR
T1 - Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor
AU - Adelaiye-Ogala, Remi
AU - Gryder, Berkley E.
AU - Nguyen, Yen Thi Minh
AU - Alilin, Aian Neil
AU - Grayson, Adlai R.
AU - Bajwa, Wardah
AU - Jansson, Keith H.
AU - Beshiri, Michael L.
AU - Agarwal, Supreet
AU - Rodriguez-Nieves, Jose Antonio
AU - Capaldo, Brian
AU - Kelly, Kathleen
AU - VanderWeele, David J.
N1 - Funding Information:
We would like to thank Dr. Charles Sawyers, Memorial Sloan Kettering Cancer Center, for providing LREX cells, and Dr. E. Corey and Dr. R.L. Vessella, The University of Washington, for providing the LuCaP models. We are grateful to the NCI Developmental Therapeutics Program for providing ipatasertib and enzalutamide used for animal studies, the CCR Genomics Core and the Illumina Sequencing Facility, Center for Cancer Research, for assistance with library preps and next-generation sequencing. This research was supported by the Intramural Research Program, NCI, NIH, Prostate Cancer Research Program, Early Investigator Research Award, W81XWH-19-1-0715 (R. Adelaiye-Ogala), the Prostate Cancer Research Program under Award No. W81XWH-13-1-0451 (D.J. VanderWeele), and the Prostate Cancer Foundation (D.J. VanderWeele).
Funding Information:
We would like to thank Dr. Charles Sawyers, Memorial Sloan Kettering Cancer Center, for providing LREX cells, and Dr. E. Corey and Dr. R.L. Vessella, The University of Washington, for providing the LuCaP models. We are grateful to the NCI Developmental Therapeutics Program for providing ipatasertib and enzaluta-mide used for animal studies, the CCR Genomics Core and the Illumina Sequencing Facility, Center for Cancer Research, for assistance with library preps and next-generation sequencing. This research was supported by the Intramural Research Program, NCI, NIH, Prostate Cancer Research Program, Early Investigator Research Award, W81XWH-19-1-0715 (R. Adelaiye-Ogala), the Prostate Cancer Research Program under Award No. W81XWH-13-1-0451 (D.J. VanderWeele), and the Prostate Cancer Foundation (D.J. VanderWeele).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087529523&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087529523&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-19-0936
DO - 10.1158/1535-7163.MCT-19-0936
M3 - Article
C2 - 32371590
AN - SCOPUS:85087529523
SN - 1535-7163
VL - 19
SP - 1436
EP - 1447
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 7
ER -