Details

Autor(en) / Beteiligte

• Du, Zhenfang
• Brown, Benjamin P
• Kim, Soyeon
• Ferguson, Donna
• Pavlick, Dean C
• Jayakumaran, Gowtham
• Benayed, Ryma
• Gallant, Jean-Nicolas
• Zhang, Yun-Kai
• Yan, Yingjun
• Red-Brewer, Monica
• Ali, Siraj M
• Schrock, Alexa B
• Zehir, Ahmet
• Ladanyi, Marc
• Smith, Adam W
• Meiler, Jens
• Lovly, Christine M

Titel

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

Ist Teil von

• Nature communications, 2021-03, Vol.12 (1), p.1382-15, Article 1382

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.