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

被引:45
作者
Du, Zhenfang [1 ]
Brown, Benjamin P. [2 ,3 ,4 ]
Kim, Soyeon [5 ]
Ferguson, Donna [6 ]
Pavlick, Dean C. [7 ]
Jayakumaran, Gowtham [6 ]
Benayed, Ryma [6 ]
Gallant, Jean-Nicolas [1 ]
Zhang, Yun-Kai [1 ]
Yan, Yingjun [1 ]
Red-Brewer, Monica [1 ]
Ali, Siraj M. [7 ]
Schrock, Alexa B. [7 ]
Zehir, Ahmet [6 ]
Ladanyi, Marc [6 ]
Smith, Adam W. [5 ]
Meiler, Jens [3 ,4 ,8 ]
Lovly, Christine M. [1 ,9 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37235 USA
[2] Vanderbilt Univ, Chem & Phys Biol Program, 221 Kirkland Hall, Nashville, TN 37235 USA
[3] Vanderbilt Univ, Dept Chem, Box 1583, Nashville, TN 37235 USA
[4] Vanderbilt Univ, Struct Biol Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA
[5] Univ Akron, Dept Chem, Akron, OH 44325 USA
[6] Mem Sloan Kettering Canc Ctr, Dept Mol Pathol, 1275 York Ave, New York, NY 10021 USA
[7] Fdn Med Inc, Cambridge, MA USA
[8] Univ Leipzig, Sch Med, Inst Drug Discovery, Leipzig, Germany
[9] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA
基金
美国国家科学基金会;
关键词
EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; JOINT-CONSENSUS-RECOMMENDATION; FACTOR RECEPTOR EGFR; MONOCLONAL-ANTIBODY; SEQUENCE VARIANTS; DUAL INHIBITION; MUTATIONS; CETUXIMAB; LANDSCAPE;
D O I
10.1038/s41467-021-21613-6
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. An EGFR mutant with kinase domain duplication (EGFR-KDD) was previously identified in an index patient, but the functional and therapeutic implications remain unclear. Here, the authors show that KDD occurs in other ErbB receptors in multiple cancers, and characterize the mechanism and inhibition of EGFR-KDD.
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页数:15
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