title: Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.
abstract: De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, University of Cardiff, King Edward VII Avenue, Cardiff CF10 3XF, UK. joneshe1@cardiff.ac.uk
authors.forename: H E
authors.initials: HE
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Goddard
authors.forename: J M W
authors.initials: JM
authors.lastname: Gee
authors.forename: S
authors.initials: S
authors.lastname: Hiscox
authors.forename: M
authors.initials: M
authors.lastname: Rubini
authors.forename: D
authors.initials: D
authors.lastname: Barrow
authors.forename: J M
authors.initials: JM
authors.lastname: Knowlden
authors.forename: S
authors.initials: S
authors.lastname: Williams
authors.forename: A E
authors.initials: AE
authors.lastname: Wakeling
authors.forename: R I
authors.initials: RI
authors.lastname: Nicholson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D018076:DNA, Complementary; D006133:Growth Substances; D011799:Quinazolines; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib