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Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

GPCRs are highly desirable drug targets for human disease. Although GPCR dysfunction drives development and progression of many tumors, including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. Here, we sought a new way of...

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Autores principales: Lyu, Cancan, Ye, Yuanchao, Lensing, Maddison M., Wagner, Kay-Uwe, Weigel, Ronald J., Chen, Songhai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492335/
https://www.ncbi.nlm.nih.gov/pubmed/34343132
http://dx.doi.org/10.1172/jci.insight.150532
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author Lyu, Cancan
Ye, Yuanchao
Lensing, Maddison M.
Wagner, Kay-Uwe
Weigel, Ronald J.
Chen, Songhai
author_facet Lyu, Cancan
Ye, Yuanchao
Lensing, Maddison M.
Wagner, Kay-Uwe
Weigel, Ronald J.
Chen, Songhai
author_sort Lyu, Cancan
collection PubMed
description GPCRs are highly desirable drug targets for human disease. Although GPCR dysfunction drives development and progression of many tumors, including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. Here, we sought a new way of blocking GPCR activation in HER2(+) BC by targeting a subgroup of GPCRs that couple to G(i/o) proteins (G(i/o)-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, G(i/o)-GPCR expression. G(i/o)-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled G(i/o)-GPCRs from their cognate G(i/o) proteins by pertussis toxin (PTx), then BC cell proliferation and migration was inhibited in vitro and HER2-driven tumor formation and metastasis were suppressed in vivo. Moreover, targeting G(i/o)-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant G(i/o)-GPCR signaling and G(i/o)-GPCR signals converge on the PI3K/AKT and Src signaling pathways to promote cancer progression and resistance to HER2-targeted therapy. Our findings point to a way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.
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spelling pubmed-84923352021-10-07 Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy Lyu, Cancan Ye, Yuanchao Lensing, Maddison M. Wagner, Kay-Uwe Weigel, Ronald J. Chen, Songhai JCI Insight Research Article GPCRs are highly desirable drug targets for human disease. Although GPCR dysfunction drives development and progression of many tumors, including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. Here, we sought a new way of blocking GPCR activation in HER2(+) BC by targeting a subgroup of GPCRs that couple to G(i/o) proteins (G(i/o)-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, G(i/o)-GPCR expression. G(i/o)-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled G(i/o)-GPCRs from their cognate G(i/o) proteins by pertussis toxin (PTx), then BC cell proliferation and migration was inhibited in vitro and HER2-driven tumor formation and metastasis were suppressed in vivo. Moreover, targeting G(i/o)-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant G(i/o)-GPCR signaling and G(i/o)-GPCR signals converge on the PI3K/AKT and Src signaling pathways to promote cancer progression and resistance to HER2-targeted therapy. Our findings point to a way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy. American Society for Clinical Investigation 2021-09-22 /pmc/articles/PMC8492335/ /pubmed/34343132 http://dx.doi.org/10.1172/jci.insight.150532 Text en © 2021 Lyu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Lyu, Cancan
Ye, Yuanchao
Lensing, Maddison M.
Wagner, Kay-Uwe
Weigel, Ronald J.
Chen, Songhai
Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title_full Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title_fullStr Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title_full_unstemmed Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title_short Targeting G(i/o) protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
title_sort targeting g(i/o) protein–coupled receptor signaling blocks her2-induced breast cancer development and enhances her2-targeted therapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492335/
https://www.ncbi.nlm.nih.gov/pubmed/34343132
http://dx.doi.org/10.1172/jci.insight.150532
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