Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors
Abstract
Purpose H1650 non-small cell lung cancer (NSCLC) cells display primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) although they have a deletion mutation on exon 19 of the EGFR gene. We investigated the effect of inhibition of both insulin-like growth factor receptor (IGFR) and EGFR signaling considering that IGFR signaling pathway has been implicated in the development and progression with therapeutic resistance of various cancers including lung cancer.Methods Three human NSCLC cell lines with an EGFR mutation of PC-9, HCC827 and H1650 were used for experiment. Cell viability and proliferative activity were assessed by MTT and three-dimensional culture assay. Combination index was obtained by CalcuSyn software. The change of EGFR- and IGFR-related signals was evaluated by western blots.Results H1650 cells were 1,000 times more resistant to gefitinib and erlotinib than HCC827 and PC-9 cells possessing the same EGFR mutation. Phosphatase and tensin homolog loss and sustained phosphorylation of Akt in spite of treatment with gefitinib were evident only in H1650 cells. Interestingly, IGFR phosphorylation was decreased by gefitinib in HCC827 and PC-9 cells while being maintained in H1650 cells. Combined treatment with the IGFR inhibitors alpha-IR3 and AG1024 enhanced gefitinib-induced growth inhibition and apoptosis, and down-regulated phosphorylation of Akt, EGFR and IGFR.Conclusion Combined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.
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Co-treatment of IGF-1R inhibitors such as α-IR3, AG1024 or R1507 with EGF-TKIs enhanced TKI-induced growth inhibition and apoptosis.
“Co-treatment of IGF-1R inhibitors such as α-IR3, AG1024 or R1507 with EGF-TKIs-enhanced TKI-induced growth inhibition and apoptosis, offering a potential new approach to overcome the resistance of EGFR-TKIs in NSCLC.50”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [50]
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- Authors
- Choi, Y. J., Rho, J. K., Jeon, B.-S., Choi, S. J., Park, S. C., Lee, S. S., Kim, H.-R., Kim, C. H., & Lee, J. C.
- Affiliations
- Korea Institute of Radiological and Medical Sciences (KR)
- Kangwon National University (KR)
- Corresponding author
- Lee, Jae Cheol
- ORCID
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2009-11-18
- Volume
- 66
- Issue
- 2
- Pages
- 381-388
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W1981984417
- Cited by
- 63
- References
- 25
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 2 · 2014: 6 · 2013: 6 · 2012: 7
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- insulin-like growth factor receptor, gefitinib, EGFR mutation, non-small cell lung cancer, primary drug resistance, EGFR tyrosine kinase inhibitors, combination therapy, AG1024, Akt phosphorylation, PTEN loss, apoptosis, H1650 cells
- MeSH terms
- Gefitinib, Antineoplastic Agents, Exons, Humans, Indicators and Reagents, Lung Neoplasms, Mutation, Quinazolines, Blotting, Western, Signal Transduction, Apoptosis, Gene Deletion, In Situ Hybridization, Fluorescence, Genes, erbB-1, Insulin-Like Growth Factor Binding Proteins, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Proto-Oncogene Proteins c-akt, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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