Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer
BackgroundHER2-positive breast cancer (BC) is highly aggressive with a poor prognosis. It is driven by HER2 oncoprotein activation/crosstalk with other receptors like EGFR/(HER1), HER3, and HER4, in addition to IGF-1R, making these receptors ideal therapeutic targets as they are expressed/overexpres...
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| مؤلفون آخرون: | , , , , , , , , |
| التنسيق: | article |
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2025
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| الوصول للمادة أونلاين: | http://dx.doi.org/10.1016/j.biopha.2025.118034 https://www.sciencedirect.com/science/article/pii/S0753332225002288 http://hdl.handle.net/10576/65155 |
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| _version_ | 1857415083822415872 |
|---|---|
| author | Kheraldine, Hadeel |
| author2 | Hassan, Arij Fouzat Saeed, Sumayyah Merhi, Maysaloun Mateo, Jericha Miles Ulamec, Monika Peric-Balja, Melita Vranic, Semir Al-Thawadi, Hamda Moustafa, Ala-Eddin Al |
| author2_role | author author author author author author author author author |
| author_facet | Kheraldine, Hadeel Hassan, Arij Fouzat Saeed, Sumayyah Merhi, Maysaloun Mateo, Jericha Miles Ulamec, Monika Peric-Balja, Melita Vranic, Semir Al-Thawadi, Hamda Moustafa, Ala-Eddin Al |
| author_role | author |
| dc.creator.none.fl_str_mv | Kheraldine, Hadeel Hassan, Arij Fouzat Saeed, Sumayyah Merhi, Maysaloun Mateo, Jericha Miles Ulamec, Monika Peric-Balja, Melita Vranic, Semir Al-Thawadi, Hamda Moustafa, Ala-Eddin Al |
| dc.date.none.fl_str_mv | 2025-05-26T06:26:17Z 2025-06-30 |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://dx.doi.org/10.1016/j.biopha.2025.118034 07533322 https://www.sciencedirect.com/science/article/pii/S0753332225002288 http://hdl.handle.net/10576/65155 187 1950-6007 |
| dc.language.none.fl_str_mv | en |
| dc.publisher.none.fl_str_mv | Elsevier |
| dc.rights.none.fl_str_mv | http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | HER2-positive breast cancer Neratinib Metformin EGFR HER3 IGF-1R Angiogenesis |
| dc.title.none.fl_str_mv | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | BackgroundHER2-positive breast cancer (BC) is highly aggressive with a poor prognosis. It is driven by HER2 oncoprotein activation/crosstalk with other receptors like EGFR/(HER1), HER3, and HER4, in addition to IGF-1R, making these receptors ideal therapeutic targets as they are expressed/overexpressed in this subtype. We postulated that targeting HER2 and IGF-1R together is a promising therapy for HER2-positive BC. Thus, we explored the outcome of a novel combination treatment using neratinib, a pan-HER inhibitor, and metformin, an IGF-1R inhibitor, on HER2-positive BC cells. Methods: In this investigation, we used cellular and molecular biology techniques in addition to an angiogenesis model and tissue microarray analysis. Results: Our data revealed that this combination therapy significantly reduced cell viability compared to individual treatments and exhibited a synergistic effect in HER2-positive BC cells. Moreover, the combination disrupted cell cycle progression and inhibited colony formation, and invasion of HER2-positive BC cells; this is accompanied by the deregulation of HER1–3 and IGF-1R expression patterns, in addition to Caspase-3, BCL2, Fascin, and Vimentin. Moreover, key regulator molecular pathways, including, ERK1/2, AKT, p38 MAPK, and mTOR, were significantly downregulated upon treatment with neratinib and metformin combination. Additionally, our data pointed out that neratinib and metformin combination inhibited angiogenesis, in-ovo, an important biological event in cancer progression. Finally, using a cohort of 55 HER2-positive BC samples, we revealed that HER2 and IGF-1R are co-expressed in most of the cases. Conclusions: These findings suggest that neratinib and metformin combination can present a promising strategy for targeting multiple pathways in HER2-positive BC. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | qu_71437615ddab1480d386f2f79c3940dc |
| identifier_str_mv | 07533322 187 1950-6007 |
| language_invalid_str_mv | en |
| network_acronym_str | qu |
| network_name_str | Qatar University repository |
| oai_identifier_str | oai:qspace.qu.edu.qa:10576/65155 |
| publishDate | 2025 |
| publisher.none.fl_str_mv | Elsevier |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| spelling | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast CancerKheraldine, HadeelHassan, Arij FouzatSaeed, SumayyahMerhi, MaysalounMateo, Jericha MilesUlamec, MonikaPeric-Balja, MelitaVranic, SemirAl-Thawadi, HamdaMoustafa, Ala-Eddin AlHER2-positive breast cancerNeratinibMetforminEGFRHER3IGF-1RAngiogenesisBackgroundHER2-positive breast cancer (BC) is highly aggressive with a poor prognosis. It is driven by HER2 oncoprotein activation/crosstalk with other receptors like EGFR/(HER1), HER3, and HER4, in addition to IGF-1R, making these receptors ideal therapeutic targets as they are expressed/overexpressed in this subtype. We postulated that targeting HER2 and IGF-1R together is a promising therapy for HER2-positive BC. Thus, we explored the outcome of a novel combination treatment using neratinib, a pan-HER inhibitor, and metformin, an IGF-1R inhibitor, on HER2-positive BC cells. Methods: In this investigation, we used cellular and molecular biology techniques in addition to an angiogenesis model and tissue microarray analysis. Results: Our data revealed that this combination therapy significantly reduced cell viability compared to individual treatments and exhibited a synergistic effect in HER2-positive BC cells. Moreover, the combination disrupted cell cycle progression and inhibited colony formation, and invasion of HER2-positive BC cells; this is accompanied by the deregulation of HER1–3 and IGF-1R expression patterns, in addition to Caspase-3, BCL2, Fascin, and Vimentin. Moreover, key regulator molecular pathways, including, ERK1/2, AKT, p38 MAPK, and mTOR, were significantly downregulated upon treatment with neratinib and metformin combination. Additionally, our data pointed out that neratinib and metformin combination inhibited angiogenesis, in-ovo, an important biological event in cancer progression. Finally, using a cohort of 55 HER2-positive BC samples, we revealed that HER2 and IGF-1R are co-expressed in most of the cases. Conclusions: These findings suggest that neratinib and metformin combination can present a promising strategy for targeting multiple pathways in HER2-positive BC.This work was funded by Qatar National Research Fund #ECRA03–003-3-002.Elsevier2025-05-26T06:26:17Z2025-06-30Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://dx.doi.org/10.1016/j.biopha.2025.11803407533322https://www.sciencedirect.com/science/article/pii/S0753332225002288http://hdl.handle.net/10576/651551871950-6007enhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:qspace.qu.edu.qa:10576/651552025-05-26T19:07:06Z |
| spellingShingle | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer Kheraldine, Hadeel HER2-positive breast cancer Neratinib Metformin EGFR HER3 IGF-1R Angiogenesis |
| status_str | publishedVersion |
| title | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| title_full | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| title_fullStr | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| title_full_unstemmed | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| title_short | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| title_sort | Neratinib and metformin: A novel therapeutic approach against HER2-Positive Breast Cancer |
| topic | HER2-positive breast cancer Neratinib Metformin EGFR HER3 IGF-1R Angiogenesis |
| url | http://dx.doi.org/10.1016/j.biopha.2025.118034 https://www.sciencedirect.com/science/article/pii/S0753332225002288 http://hdl.handle.net/10576/65155 |