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.
Highlights
Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies
We evaluate the prevalence of Kinase domain duplications (KDDs) in ERBB family members (EGFR/EGFR, ERBB2/HER2, ERBB3/ HER3, and ERBB4/HER4) across multiple types of human cancers in order to refine our understanding of KDD as an oncogenic driver
We observed lower incidences of KDD in ERBB2, ERBB3 and ERBB4 than EGFR, with distributions mirroring those of other observed oncogenic mutations in brain tumors and NSCLC13–17 (Table 1a)
Summary
Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. 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. Numerous studies have shown that patients with EGFR kinase domain mutations benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs), whereas patients with tumors containing wild-type EGFR do not derive benefit[10]. We combine structural modeling, biochemical assays, and experimental and computational biophysical analyses to understand the mechanism whereby EGFR-KDD aberrantly activates EGFR These complementary approaches suggest that EGFR-KDD is activated through the formation of ligand-independent intra-molecular dimers and signaling is amplified through ligand-dependent inter-molecular dimers/ multimers. We show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra-molecular and inter-molecular dimerization These studies have important implications for the treatment of patients whose tumor harbor EGFR-KDD
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