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Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers

Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms...

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Autores principales: Maxwell, Pamela J., McKechnie, Melanie, Armstrong, Christopher W., Manley, Judith M., Ong, Chee Wee, Worthington, Jenny, Mills, Ian G., Longley, Daniel B., Quigley, James P., Zoubeidi, Amina, de Bono, Johann S., Deryugina, Elena, LaBonte, Melissa J., Waugh, David J.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381111/
https://www.ncbi.nlm.nih.gov/pubmed/35302608
http://dx.doi.org/10.1158/1541-7786.MCR-21-0780
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author Maxwell, Pamela J.
McKechnie, Melanie
Armstrong, Christopher W.
Manley, Judith M.
Ong, Chee Wee
Worthington, Jenny
Mills, Ian G.
Longley, Daniel B.
Quigley, James P.
Zoubeidi, Amina
de Bono, Johann S.
Deryugina, Elena
LaBonte, Melissa J.
Waugh, David J.J.
author_facet Maxwell, Pamela J.
McKechnie, Melanie
Armstrong, Christopher W.
Manley, Judith M.
Ong, Chee Wee
Worthington, Jenny
Mills, Ian G.
Longley, Daniel B.
Quigley, James P.
Zoubeidi, Amina
de Bono, Johann S.
Deryugina, Elena
LaBonte, Melissa J.
Waugh, David J.J.
author_sort Maxwell, Pamela J.
collection PubMed
description Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumor microenvironment, will extend the clinical benefit of AR-targeted therapy. Here, we show the ASI enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR expression in CD34(+) vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVECs in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Coinhibition of IL8 and VEGF-A restored tumor response in the presence of enzalutamide, confirming the functional importance of their elevated expression in enzalutamide-resistant models. Moreover, coinhibition of IL8 and VEGF-A resulted in a durable, effective resolution of enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia-induced factors, IL8 and VEGF-A, prolongs tumor sensitivity to enzalutamide in preclinical models and may delay the onset of enzalutamide resistance. IMPLICATIONS: Targeting hypoxia-induced signaling may extend the therapeutic benefit of enzalutamide, providing an improved treatment strategy for patients with resistant disease.
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spelling pubmed-93811112023-01-05 Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers Maxwell, Pamela J. McKechnie, Melanie Armstrong, Christopher W. Manley, Judith M. Ong, Chee Wee Worthington, Jenny Mills, Ian G. Longley, Daniel B. Quigley, James P. Zoubeidi, Amina de Bono, Johann S. Deryugina, Elena LaBonte, Melissa J. Waugh, David J.J. Mol Cancer Res Cancer Genes and Networks Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumor microenvironment, will extend the clinical benefit of AR-targeted therapy. Here, we show the ASI enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR expression in CD34(+) vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVECs in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Coinhibition of IL8 and VEGF-A restored tumor response in the presence of enzalutamide, confirming the functional importance of their elevated expression in enzalutamide-resistant models. Moreover, coinhibition of IL8 and VEGF-A resulted in a durable, effective resolution of enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia-induced factors, IL8 and VEGF-A, prolongs tumor sensitivity to enzalutamide in preclinical models and may delay the onset of enzalutamide resistance. IMPLICATIONS: Targeting hypoxia-induced signaling may extend the therapeutic benefit of enzalutamide, providing an improved treatment strategy for patients with resistant disease. American Association for Cancer Research 2022-06-03 2022-03-18 /pmc/articles/PMC9381111/ /pubmed/35302608 http://dx.doi.org/10.1158/1541-7786.MCR-21-0780 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Cancer Genes and Networks
Maxwell, Pamela J.
McKechnie, Melanie
Armstrong, Christopher W.
Manley, Judith M.
Ong, Chee Wee
Worthington, Jenny
Mills, Ian G.
Longley, Daniel B.
Quigley, James P.
Zoubeidi, Amina
de Bono, Johann S.
Deryugina, Elena
LaBonte, Melissa J.
Waugh, David J.J.
Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title_full Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title_fullStr Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title_full_unstemmed Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title_short Attenuating Adaptive VEGF-A and IL8 Signaling Restores Durable Tumor Control in AR Antagonist–Treated Prostate Cancers
title_sort attenuating adaptive vegf-a and il8 signaling restores durable tumor control in ar antagonist–treated prostate cancers
topic Cancer Genes and Networks
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381111/
https://www.ncbi.nlm.nih.gov/pubmed/35302608
http://dx.doi.org/10.1158/1541-7786.MCR-21-0780
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