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

Paola Vermeer, Paul L. Colbert, Bryant G. Wieking, Daniel W. Vermeer, John H. Lee

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5787-5797
Number of pages11
JournalCancer Research
Volume73
Issue number18
DOIs
StatePublished - Sep 15 2013

Fingerprint

Epidermal Growth Factor Receptor
Neoplasms
Dimerization
Drug Resistance
Phosphorylation
Growth
Pharmaceutical Preparations
Cetuximab
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex. / Vermeer, Paola; Colbert, Paul L.; Wieking, Bryant G.; Vermeer, Daniel W.; Lee, John H.

In: Cancer Research, Vol. 73, No. 18, 15.09.2013, p. 5787-5797.

Research output: Contribution to journalArticle

Vermeer, Paola ; Colbert, Paul L. ; Wieking, Bryant G. ; Vermeer, Daniel W. ; Lee, John H. / Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex. In: Cancer Research. 2013 ; Vol. 73, No. 18. pp. 5787-5797.
@article{a1b0b019133d49979dcdf4b0a7beab04,
title = "Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex",
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.",
author = "Paola Vermeer and Colbert, {Paul L.} and Wieking, {Bryant G.} and Vermeer, {Daniel W.} and Lee, {John H.}",
year = "2013",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-13-0760",
language = "English (US)",
volume = "73",
pages = "5787--5797",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex

AU - Vermeer, Paola

AU - Colbert, Paul L.

AU - Wieking, Bryant G.

AU - Vermeer, Daniel W.

AU - Lee, John H.

PY - 2013/9/15

Y1 - 2013/9/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84884759741&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884759741&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-13-0760

DO - 10.1158/0008-5472.CAN-13-0760

M3 - Article

VL - 73

SP - 5787

EP - 5797

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -