Cited by 170HER2/EGFR in Cancer ResearchColorectal Cancer Treatments and StudiesLung Cancer Treatments and Mutations

Epidermal Growth Factor Receptor (EGFR) Ubiquitination as a Mechanism of Acquired Resistance Escaping Treatment by the Anti-EGFR Monoclonal Antibody Cetuximab

Lu, Yang, Li, Xinqun, Liang, Ke, Luwor, Rodney, Siddik, Zahid H., Mills, Gordon B., Mendelsohn, John, Fan, Zhen·2007·Cancer Research

Abstract

Cetuximab is an epidermal growth factor receptor (EGFR)–blocking antibody that has been approved for treatment of patients with metastatic colorectal cancer. In this study, we investigated biochemical changes in signaling pathways of a cetuximab-resistant subline of DiFi colorectal cancer cells (DiFi5) that was developed by exposing the parental sensitive cells to subeffective doses of cetuximab over an extended period of time. Compared with parental DiFi cells that express high levels of EGFR and in which cetuximab induces apoptosis, the cetuximab-resistant DiFi5 cells showed markedly lower protein levels of EGFR, an increased association of EGFR with Cbl, and an increased ubiquitination of EGFR. DiFi5 cells also had a markedly higher level of Src-Y416 phosphorylation both at baseline and on EGF stimulation. Although EGFR levels were low, DiFi5 cells responded to EGF stimulation with robust phosphorylation of EGFR on Y845 and strong phosphorylation of Akt and extracellular signal–regulated kinase, comparable to those of parental cells. Most importantly, inhibition of Src kinase activity with PP2 reversed the resistance of DiFi5 cells to cetuximab-induced apoptosis without affecting the levels of EGFR in the cells. Our results indicate that colorectal cancer cells may develop acquired resistance to cetuximab via altering EGFR levels through promotion of EGFR ubiquitination and degradation and using Src kinase-mediated cell signaling to bypass their dependency on EGFR for cell growth and survival. [Cancer Res 2007;67(17):8240–7]

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Crossref · 10.1158/0008-5472.can-07-0589

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Authors
Lu, Y., Li, X., Liang, K., Luwor, R., Siddik, Z. H., Mills, G. B., Mendelsohn, J., & Fan, Z.
Affiliations
  • 1Experimental Therapeutics and Departments of
  • The University of Texas Health Science Center at Houston (US)
  • The University of Texas MD Anderson Cancer Center (US)
Venue
Cancer Research
Published
2007-09-01
Volume
67
Issue
17
Pages
8240-8247
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
OpenAlex
W2107693250
Cited by
170
References
34
Citations by year
2026: 5 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 13 · 2014: 20 · 2013: 9 · 2012: 10
FWCI
7.74
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
cetuximab, EGFR, acquired drug resistance, ubiquitination, EGFR degradation, Src kinase, CBL, colorectal cancer, EGF signaling, Akt, ERK, apoptosis, monoclonal antibody therapy
MeSH terms
Cetuximab, Adenocarcinoma, Antibodies, Monoclonal, Humans, Protein Processing, Post-Translational, Tumor Cells, Cultured, Colorectal Neoplasms, Signal Transduction, Drug Resistance, Neoplasm, src-Family Kinases, Ubiquitin, Antibodies, Monoclonal, Humanized, ErbB Receptors

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