The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins
Open accessAbstract
Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.
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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
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Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
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Self-citationPao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
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Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors
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Cited by
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002003 · Cited by 3,499
Self-citationTargeting PI3K signalling in cancer: opportunities, challenges and limitations
Engelman, J. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2664 · Cited by 2,445
Self-citationInsulin and insulin-like growth factor signalling in neoplasia
Pollak, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2536 · Cited by 2,059
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083
“Increased IGF1R signalling has also been associated with acquired resistance, albeit only in an in vitro model using a cell line that expressed high levels of wild-type EGF”
Background
Metadata
- Authors
- Guix, M., Faber, A. C., Wang, S. E., Olivares, M. G., Song, Y., Qu, S., Rinehart, C., Seidel, B., Yee, D., Arteaga, C. L., & Engelman, J. A.
- Venue
- Journal of Clinical Investigation
- Published
- 2008-06-01
- Volume
- 118
- Issue
- 7
- Pages
- 2609-19
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2171313739
- Cited by
- 521
- References
- 10
- FWCI
- 28.64
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. https://app.cochat.ai/papers/10.1172/jci34588
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- Guix, M., Faber, A. C., Wang, S. E., Olivares, M. G., Song, Y., Qu, S., Rinehart, C., Seidel, B., Yee, D., Arteaga, C. L., & Engelman, J. A. (2008). Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. Journal of Clinical Investigation. https://doi.org/10.1172/jci34588
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
