Cargando…
Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants
Genomic 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 b...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496187/ https://www.ncbi.nlm.nih.gov/pubmed/25826094 |
_version_ | 1782380364476448768 |
---|---|
author | Park, Angela K.J. Francis, Joshua M. Park, Woong-Yang Park, Joon-Oh Cho, Jeonghee |
author_facet | Park, Angela K.J. Francis, Joshua M. Park, Woong-Yang Park, Joon-Oh Cho, Jeonghee |
author_sort | Park, Angela K.J. |
collection | PubMed |
description | Genomic 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. |
format | Online Article Text |
id | pubmed-4496187 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44961872015-07-10 Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants Park, Angela K.J. Francis, Joshua M. Park, Woong-Yang Park, Joon-Oh Cho, Jeonghee Oncotarget Research Paper Genomic 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. Impact Journals LLC 2015-03-12 /pmc/articles/PMC4496187/ /pubmed/25826094 Text en Copyright: © 2015 Park et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Park, Angela K.J. Francis, Joshua M. Park, Woong-Yang Park, Joon-Oh Cho, Jeonghee Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title | Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title_full | Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title_fullStr | Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title_full_unstemmed | Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title_short | Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
title_sort | constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496187/ https://www.ncbi.nlm.nih.gov/pubmed/25826094 |
work_keys_str_mv | AT parkangelakj constitutiveasymmetricdimerizationdrivesoncogenicactivationofepidermalgrowthfactorreceptorcarboxylterminaldeletionmutants AT francisjoshuam constitutiveasymmetricdimerizationdrivesoncogenicactivationofepidermalgrowthfactorreceptorcarboxylterminaldeletionmutants AT parkwoongyang constitutiveasymmetricdimerizationdrivesoncogenicactivationofepidermalgrowthfactorreceptorcarboxylterminaldeletionmutants AT parkjoonoh constitutiveasymmetricdimerizationdrivesoncogenicactivationofepidermalgrowthfactorreceptorcarboxylterminaldeletionmutants AT chojeonghee constitutiveasymmetricdimerizationdrivesoncogenicactivationofepidermalgrowthfactorreceptorcarboxylterminaldeletionmutants |