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

Zhenfang Du, Benjamin P. Brown, Soyeon Kim, Donna Ferguson, Dean C. Pavlick, Gowtham Jayakumaran, Ryma Benayed, Jean-Nicolas Gallant, Yun-Kai Zhang, Yingjun Yan, Monica Red-Brewer, Siraj M. Ali, Alexa B. Schrock, Ahmet Zehir, Marc Ladanyi, Adam W. Smith, Jens Meiler () and Christine M. Lovly ()
Additional contact information
Zhenfang Du: Vanderbilt University Medical Center
Benjamin P. Brown: Vanderbilt University
Soyeon Kim: University of Akron
Donna Ferguson: Memorial Sloan Kettering Cancer Center
Dean C. Pavlick: Foundation Medicine, Inc.
Gowtham Jayakumaran: Memorial Sloan Kettering Cancer Center
Ryma Benayed: Memorial Sloan Kettering Cancer Center
Jean-Nicolas Gallant: Vanderbilt University Medical Center
Yun-Kai Zhang: Vanderbilt University Medical Center
Yingjun Yan: Vanderbilt University Medical Center
Monica Red-Brewer: Vanderbilt University Medical Center
Siraj M. Ali: Foundation Medicine, Inc.
Alexa B. Schrock: Foundation Medicine, Inc.
Ahmet Zehir: Memorial Sloan Kettering Cancer Center
Marc Ladanyi: Memorial Sloan Kettering Cancer Center
Adam W. Smith: University of Akron
Jens Meiler: Vanderbilt University
Christine M. Lovly: Vanderbilt University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21613-6

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DOI: 10.1038/s41467-021-21613-6

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