Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting Journal Article

   


Authors: Du, Z.; Brown, B. P.; Kim, S.; Ferguson, D.; Pavlick, D. C.; Jayakumaran, G.; Benayed, R.; Gallant, J. N.; Zhang, Y. K.; Yan, Y.; Red-Brewer, M.; Ali, S. M.; Schrock, A. B.; Zehir, A.; Ladanyi, M.; Smith, A. W.; Meiler, J.; Lovly, C. M.
Article Title: Structure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting
Abstract: Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers. © 2021, The Author(s).
Keywords: genetics; protein domain; neoplasm; neoplasms; cell proliferation; mouse; animal; metabolism; animals; mice; gene expression; epidermal growth factor receptor; cell line; protein binding; enzyme activity; structure activity relation; structure-activity relationship; phosphorylation; oncogenes; oncogene; chemistry; amino acid sequence; protein multimerization; epitope; ligand; molecular analysis; gene duplication; ligands; biochemistry; disease treatment; protein domains; ontogeny; epitopes; molecularly targeted therapy; molecular targeted therapy; erbb receptors; structural analysis
Journal Title: Nature Communications
Volume: 12
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2021-03-02
Start Page: 1382
Language: English
DOI: 10.1038/s41467-021-21613-6
PUBMED: 33654076
PROVIDER: scopus
PMCID: PMC7925532
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85101972337&doi=10.1038%2fs41467-021-21613-6&partnerID=40&md5=7f81ac1e9f110b00cf96881ffea18e05
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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MSK Authors
  1. Marc Ladanyi
    1329 Ladanyi
  2. Ahmet Zehir
    344 Zehir
  3. Rym Benayed
    188 Benayed
  4. Gowtham Jayakumaran
    45 Jayakumaran
  5. Donna Catherine Ferguson
    12 Ferguson
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