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

doi:10.1158/1535-7163.MCT-19-0936

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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

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 language	English (US)
Pages (from-to)	1436-1447
Number of pages	12
Journal	Molecular cancer therapeutics
Volume	19
Issue number	7
DOIs	https://doi.org/10.1158/1535-7163.MCT-19-0936
State	Published - Jul 1 2020

Funding

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). 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).

ASJC Scopus subject areas

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1535-7163.MCT-19-0936

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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

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title = "Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

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doi = "10.1158/1535-7163.MCT-19-0936",

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Adelaiye-Ogala, R, Gryder, BE, Nguyen, YTM, Alilin, AN, Grayson, AR, Bajwa, W, Jansson, KH, Beshiri, ML, Agarwal, S, Rodriguez-Nieves, JA, Capaldo, B, Kelly, K & VanderWeele, DJ 2020, 'Targeting the PI3K/AKT pathway overcomes enzalutamide resistance by inhibiting induction of the glucocorticoid receptor', Molecular cancer therapeutics, vol. 19, no. 7, pp. 1436-1447. https://doi.org/10.1158/1535-7163.MCT-19-0936

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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.

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.

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

Abstract

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