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

Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, Rinehart C, Seidel B, Yee D, Arteaga CL, Engelman JA
J Clin Invest. 2008 118 (7): 2609-19

PMID: 18568074 · PMCID: PMC2430495 · DOI:10.1172/JCI34588

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.

MeSH Terms (27)

Adaptor Proteins, Signal Transducing Animals Carcinoma, Squamous Cell Cell Line, Tumor Cell Survival Drug Resistance, Neoplasm ErbB Receptors Female Gefitinib Gene Expression Humans Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor Binding Protein 4 Insulin-Like Growth Factor Binding Proteins Insulin-Like Growth Factor I Insulin-Like Growth Factor II Insulin Receptor Substrate Proteins Mice Mice, Nude Phosphatidylinositol 3-Kinases Phosphorylation Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt Quinazolines Receptor, ErbB-3 Receptor, IGF Type 1 Xenograft Model Antitumor Assays

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