Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins

Marta Guix, Anthony C. Faber, Shizhen Emily Wang, Maria Graciela Olivares, Youngchul Song, Sherman Qu, Cammie Rinehart, Brenda Seidel, Douglas Yee, Carlos L. Arteaga, Jeffrey A. Engelman

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Abstract

Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFRTKI 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.

Original languageEnglish (US)
Pages (from-to)2609-2619
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number7
DOIs
StatePublished - Jul 1 2008

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Insulin-Like Growth Factor Binding Proteins
Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinases
Neoplasms
Insulin-Like Growth Factor Binding Protein 3
Down-Regulation
Insulin-Like Growth Factor Binding Protein 4
gefitinib
Squamous Cell Neoplasms
Growth
Recombinant Proteins
Drug Resistance
Heterografts
Monoclonal Antibodies
Phosphorylation
RNA
Gene Expression
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

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Guix, M., Faber, A. C., Wang, S. E., Olivares, M. G., Song, Y., Qu, S., ... 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, 118(7), 2609-2619. https://doi.org/10.1172/JC134588

Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. / Guix, Marta; Faber, Anthony C.; Wang, Shizhen Emily; Olivares, Maria Graciela; Song, Youngchul; Qu, Sherman; Rinehart, Cammie; Seidel, Brenda; Yee, Douglas; Arteaga, Carlos L.; Engelman, Jeffrey A.

In: Journal of Clinical Investigation, Vol. 118, No. 7, 01.07.2008, p. 2609-2619.

Research output: Contribution to journalArticle

Guix, M, Faber, AC, Wang, SE, Olivares, MG, Song, Y, Qu, S, Rinehart, C, Seidel, B, Yee, D, Arteaga, CL & Engelman, JA 2008, 'Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins', Journal of Clinical Investigation, vol. 118, no. 7, pp. 2609-2619. https://doi.org/10.1172/JC134588
Guix, Marta ; Faber, Anthony C. ; Wang, Shizhen Emily ; Olivares, Maria Graciela ; Song, Youngchul ; Qu, Sherman ; Rinehart, Cammie ; Seidel, Brenda ; Yee, Douglas ; Arteaga, Carlos L. ; Engelman, Jeffrey A. / Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 7. pp. 2609-2619.
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