Research Papers:

Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants

Angela K.J. Park, Joshua M. Francis, Woong-Yang Park, Joon-Oh Park and Jeonghee Cho _

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Oncotarget. 2015; 6:8839-8850. https://doi.org/10.18632/oncotarget.3559

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Angela K.J. Park1,2, Joshua M. Francis3, Woong-Yang Park1,2, Joon-Oh Park4 and Jeonghee Cho1,2

1 Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea

2 Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea

3 The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

4 Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

Correspondence to:

Jeonghee Cho, email:

Keywords: epidermal growth factor receptor, EGFR targeted therapy, asymmetric dimerization, EGFR C-terminal domain deletion

Received: December 30, 2014 Accepted: February 12, 2015 Published: March 12, 2015


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.

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