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dc.contributor.authorPark, Angela K.J.en_US
dc.contributor.authorFrancis, Joshua M.en_US
dc.contributor.authorPark, Woong-Yangen_US
dc.contributor.authorPark, Joon-Ohen_US
dc.contributor.authorCho, Jeongheeen_US
dc.date.accessioned2015-08-03T14:02:35Z
dc.date.issued2015en_US
dc.identifier.citationPark, Angela K.J., Joshua M. Francis, Woong-Yang Park, Joon-Oh Park, and Jeonghee Cho. 2015. “Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants.” Oncotarget 6 (11): 8839-8850.en
dc.identifier.issn1949-2553en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820913
dc.description.abstractGenomic alterations targeting the Epidermal Growth Factor Receptor (EGFR) gene have been strongly associated with cancer pathogenesis. The clinical effectiveness of EGFR targeted therapies, including small molecules directed against the kinase domain such as gefitinib, erlotinib and afatinib, have been proven successful in treating non-small cell lung cancer patients with tumors harboring EGFR kinase domain mutations. Recent large-scale genomic studies in glioblastoma and lung cancer have identified an additional class of oncogenic mutations caused by the intragenic deletion of carboxy-terminal coding regions. Here, we report that combinations of exonic deletions of exon 25 to 28 lead to the oncogenic activation of EGF receptor in the absence of ligand and consequent cellular transformation, indicating a significant role of C-terminal domain in modulating EGFR activation. Furthermore, we show that the oncogenic activity of the resulting C-terminal deletion mutants are efficiently inhibited by EGFR-targeted drugs including erlotinib, afatinib, dacomitinib as well as cetuximab, expanding the therapeutic rationale of cancer genome-based EGFR targeted approaches. Finally, in vivo and in vitro preclinical studies demonstrate that constitutive asymmetric dimerization in mutant EGFR is a key mechanism for oncogenic activation and tumorigenesis by C-terminal deletion mutants. Therefore, our data provide compelling evidence for oncogenic activation of C-terminal deletion mutants at the molecular level and we propose that C-terminal deletion status of EGFR can be considered as a potential genomic marker for EGFR-targeted therapy.en
dc.language.isoen_USen
dc.publisherImpact Journals LLCen
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496187/pdf/en
dash.licenseLAAen_US
dc.subjectepidermal growth factor receptoren
dc.subjectEGFR targeted therapyen
dc.subjectasymmetric dimerizationen
dc.subjectEGFR C-terminal domain deletionen
dc.titleConstitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutantsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalOncotargeten
dash.depositing.authorFrancis, Joshua M.en_US
dc.date.available2015-08-03T14:02:35Z
dash.authorsorderedfalse
dash.contributor.affiliatedFrancis, Joshua M.


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