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Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex.

Authors
Type
Published Article
Journal
Cancer Research
0008-5472
Publisher
American Association for Cancer Research
Publication Date
Volume
73
Issue
18
Pages
5787–5797
Identifiers
DOI: 10.1158/0008-5472.CAN-13-0760
PMID: 23811940
Source
Medline

Abstract

Most squamous cell carcinomas of the head and neck (HNSCC) overexpress ERBB1/EGFR, but EGF receptor (EGFR)-targeted therapies have yielded disappointing clinical results in treatment of this cancer. Here, we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the presence of cetuximab. Mechanistically, cetuximab drives a shift in EGFR dimerization partners within the signaling complex, suggesting that targeted drugs may trigger partner rearrangements that allow persistent pathway activation. EFNB1 attenuation slowed tumor growth and increased survival in a murine model of HNSCC, suggesting a substantial contribution of EFNB1 signaling to HNSCC development. Together, our findings suggest that EFNB1 is part of the EGFR signaling complex and may mediate drug resistance in HNSCC as well as other solid tumors.

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