Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity
DC Field | Value | Language |
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dc.contributor.author | Hanker, Ariella B. | - |
dc.contributor.author | Brown, Benjamin P. | - |
dc.contributor.author | Meiler, Jens | - |
dc.contributor.author | Marin, Arnaldo | - |
dc.contributor.author | Jayanthan, Harikrishna S. | - |
dc.contributor.author | Ye, Dan | - |
dc.contributor.author | Lin, Chang-Ching | - |
dc.contributor.author | Akamatsu, Hiroaki | - |
dc.contributor.author | Lee, Kyung-Min | - |
dc.contributor.author | Chatterjee, Sumanta | - |
dc.contributor.author | Sudhan, Dhivya R. | - |
dc.contributor.author | Servetto, Alberto | - |
dc.contributor.author | Brewer, Monica Red | - |
dc.contributor.author | Koch, James P. | - |
dc.contributor.author | Sheehan, Jonathan H. | - |
dc.contributor.author | He, Jie | - |
dc.contributor.author | Lalani, Alshad S. | - |
dc.contributor.author | Arteaga, Carlos L. | - |
dc.date.accessioned | 2022-07-06T15:57:40Z | - |
dc.date.available | 2022-07-06T15:57:40Z | - |
dc.date.created | 2021-11-22 | - |
dc.date.issued | 2021-08 | - |
dc.identifier.issn | 1535-6108 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/141325 | - |
dc.description.abstract | Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3(E928G) kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3K alpha inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | CELL PRESS | - |
dc.title | Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, Kyung-Min | - |
dc.identifier.doi | 10.1016/j.ccell.2021.06.001 | - |
dc.identifier.scopusid | 2-s2.0-85111914984 | - |
dc.identifier.wosid | 000684448300019 | - |
dc.identifier.bibliographicCitation | CANCER CELL, v.39, no.8, pp.1099 - 1114+e8 | - |
dc.relation.isPartOf | CANCER CELL | - |
dc.citation.title | CANCER CELL | - |
dc.citation.volume | 39 | - |
dc.citation.number | 8 | - |
dc.citation.startPage | 1099 | - |
dc.citation.endPage | 1114+e8 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.subject.keywordPlus | KINASE INHIBITION | - |
dc.subject.keywordPlus | PAN-HER | - |
dc.subject.keywordPlus | BREAST | - |
dc.subject.keywordPlus | MECHANISM | - |
dc.subject.keywordPlus | TRASTUZUMAB | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | NERATINIB | - |
dc.subject.keywordPlus | DYNAMICS | - |
dc.subject.keywordPlus | GROWTH | - |
dc.subject.keywordPlus | DOMAIN | - |
dc.subject.keywordAuthor | breast cancer | - |
dc.subject.keywordAuthor | HER2 | - |
dc.subject.keywordAuthor | HER3 | - |
dc.subject.keywordAuthor | molecular dynamics | - |
dc.subject.keywordAuthor | neratinib | - |
dc.subject.keywordAuthor | personalized structural biology | - |
dc.subject.keywordAuthor | PI3K | - |
dc.subject.keywordAuthor | precision oncology | - |
dc.subject.keywordAuthor | Rosetta | - |
dc.identifier.url | https://www.sciencedirect.com/science/article/pii/S1535610821002841?via%3Dihub | - |
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