Vascular Endothelial Growth Factor Receptor-1 Contributes to Resistance to Anti–Epidermal Growth Factor Receptor Drugs in Human Cancer Cells
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Abstract
Purpose: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor–resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. Experimental Design: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways. Results: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor–resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. Conclusions: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.
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Increased expression of pro-angiogenic ligands and cognate receptors (including VEGFs, VEGFRs, and Eph receptors) may dictate sensitivity to anti-EGFR therapy in colorectal tumors.
“taken together, these findings suggest that increased expression of pro-angiogenic ligands and cognate receptors (including VEGFs, VEGFRs, and Eph receptors) may dictate sensitivity to anti-EGFR therapy in colorectal tumors.”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [127]
Altered tumor angiogenesis as a way to escape cetuximab antitumor activity has been reported in colorectal cancer cellular models and ascribed to either VEGF protein overexpression or increased VEGFR-1 and VEGFR-2 activation.
“Biologically, altered tumor angiogenesis as a way to escape cetuximab antitumor activity has been previously reported in CRC cellular models and ascribed to either VEGF protein overexpression or increased VEGFR-1 and VEGFR-2 activation [126, 127]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [127]
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- Authors
- Bianco, R., Rosa, R., Damiano, V., Daniele, G., Gelardi, T., Garofalo, S., Tarallo, V., De Falco, S., Melisi, D., Benelli, R., Albini, A., Ryan, A., Ciardiello, F., & Tortora, G.
- Affiliations
- University of Naples Federico II (IT)
- Institute of Genetics and Biophysics (IT)
- 2Institute of Genetics and Biophysics “A. Buzzati Traverso,” Consiglio Nazionale delle Ricerche;
- 4Oncologia Sperimentale-A, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;
- MultiMedica (IT)
- AstraZeneca (United Kingdom) (GB)
- University of Campania "Luigi Vanvitelli" (IT)
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2008-08-12
- Volume
- 14
- Issue
- 16
- Pages
- 5069-5080
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2124003148
- Cited by
- 149
- References
- 52
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 7 · 2019: 9 · 2018: 6 · 2017: 3 · 2016: 5 · 2015: 13 · 2014: 14 · 2013: 16 · 2012: 13
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- VEGFR1, Flt-1, EGFR inhibitor resistance, vandetanib, EGFR, Akt signaling, p70 S6 kinase, vascular endothelial growth factor, placental growth factor, cell migration, cancer cell lines, colon cancer, prostate cancer, breast cancer, RET, VEGFR2
- MeSH terms
- Antineoplastic Agents, Cell Adhesion, Cell Movement, Humans, Neoplasms, Piperidines, Quinazolines, Transfection, Blotting, Western, Signal Transduction, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Vascular Endothelial Growth Factor Receptor-1, Cell Line, Tumor, Immunoprecipitation, Cell Proliferation, ErbB Receptors
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