Targeting Gi/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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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.150532 |
| _version_ | 1811227814180945920 |
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| author | Cancan Lyu Yuanchao Ye Maddison M. Lensing Kay-Uwe Wagner Ronald J. Weigel Songhai Chen |
| author_facet | Cancan Lyu Yuanchao Ye Maddison M. Lensing Kay-Uwe Wagner Ronald J. Weigel Songhai Chen |
| author_sort | Cancan Lyu |
| collection | DOAJ |
| 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 Gi/o proteins (Gi/o-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCR expression. Gi/o-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled Gi/o-GPCRs from their cognate Gi/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 Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant Gi/o-GPCR signaling and Gi/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. |
| first_indexed | 2024-04-12T09:48:13Z |
| format | Article |
| id | doaj.art-e847b129bf434051bc84d8e6abd7ee2b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:48:13Z |
| publishDate | 2021-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-e847b129bf434051bc84d8e6abd7ee2b2022-12-22T03:37:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-09-01618Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapyCancan LyuYuanchao YeMaddison M. LensingKay-Uwe WagnerRonald J. WeigelSonghai ChenGPCRs 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 Gi/o proteins (Gi/o-GPCRs). In mammary epithelial cells of transgenic mouse models, and BC cell lines, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCR expression. Gi/o-GPCR stimulation transactivated EGFR and HER2 and activated the PI3K/AKT and Src pathways. If we uncoupled Gi/o-GPCRs from their cognate Gi/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 Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that, in BC cells, HER2 hyperactivation drives aberrant Gi/o-GPCR signaling and Gi/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.https://doi.org/10.1172/jci.insight.150532OncologyTherapeutics |
| spellingShingle | Cancan Lyu Yuanchao Ye Maddison M. Lensing Kay-Uwe Wagner Ronald J. Weigel Songhai Chen Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy JCI Insight Oncology Therapeutics |
| title | Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
| title_full | Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
| title_fullStr | Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
| title_full_unstemmed | Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
| title_short | Targeting Gi/o protein–coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy |
| title_sort | targeting gi o protein coupled receptor signaling blocks her2 induced breast cancer development and enhances her2 targeted therapy |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.150532 |
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