Epidermal Growth Factor Receptor cooperates with Src Family Kinases in acquired resistance to cetuximab
Open accessAbstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.
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The combination of cetuximab and dasatinib has been shown to be effective in overcoming acquired resistance to cetuximab in NSCLC.
“The combination of cetuximab and dasatinib has shown to be effective in other circumstances these include in the situation of overcoming acquired resistance to cetuximab in NSCLC (Li et al., 2009; Wheeler et al., 2009).”
From Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab (2011) · cites this paper as Wheeler et al., 2009
In NCI-H226 lung cancer cells, c-src expression increases after long-term exposure to an EGFR inhibitory antibody; SFKs also show increased activity in cetuximab-resistant cells followed by increased sensitivity to dasatinib.
“In NCI-H226 lung cancer cells, c-src expression is increased after long-term exposure to an EGFR inhibitory antibody.SFKs also show increased activity in cetuximab-resistant cells followed by respective increased sensitivity to dasatinib.98”
From The molecular rationale of Src inhibition in colorectal carcinomas (2014) · cites this paper as [98]
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- [20]Wheeler DL Huang S Kruser TJ Nechrebecki MM Armstrong EA Benavente S Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members Oncogene 2008 PMC2903615 18297114
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- Authors
- Wheeler, D. L., Iida, M., Kruser, T. J., Nechrebecki, M. M., Dunn, E. F., Armstrong, E. A., Huang, S., & Harari, P. M.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Wheeler, Deric L.
- Venue
- Cancer Biology & Therapy
- Publisher
- Informa UK Limited
- Published
- 2009-04-15
- Volume
- 8
- Issue
- 8
- Pages
- 696-703
- ISSN
- 1538-4047 (ISSN-L)
- 1555-8576
- PMC
- PMC2895567
- OpenAlex
- W2042327295
- Cited by
- 157
- References
- 28
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 11 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 11 · 2015: 9 · 2014: 23 · 2013: 12 · 2012: 15
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Biology & Therapy (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amgen
- AstraZeneca
- National Institutes of Health
- Genentech
- National Cancer Institute (R01CA113448, P30CA014520)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- epidermal growth factor receptor, Src family kinases, cetuximab resistance, acquired drug resistance, HER3, PI3K/Akt signaling, dasatinib, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, combination therapy
- MeSH terms
- Cetuximab, Dasatinib, Antibodies, Monoclonal, Carcinoma, Non-Small-Cell Lung, Drug Therapy, Combination, Flow Cytometry, Humans, Lung Neoplasms, Pyrimidines, Thiazoles, Immunoblotting, Drug Resistance, Neoplasm, src-Family Kinases, Phosphatidylinositol 3-Kinases, Receptor, ErbB-3, Cell Line, Tumor, Protein Kinase Inhibitors, Immunoprecipitation, Cell Proliferation, Proto-Oncogene Proteins c-akt, Antibodies, Monoclonal, Humanized, ErbB Receptors
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