Insulin like growth factor I receptor signalling and acquired resistance to gefitinib (ZD1839, Iressa) in human breast and prostate cancer cells英文电子书.pdfVIP

Endocrine-Related Cancer (2004) 11 793–814 Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells 1 H E Jones, L Goddard, J M W Gee, S Hiscox, M Rubini , D Barrow, J M Knowlden, S Williams, A E Wakeling 2 and R I Nicholson Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, University of Cardiff, King Edward VII Avenue, Cardiff CF10 3XF, UK 1Dipartimento di Medicina Sperimentale e Diagnostica, Universita di Ferrara, Ferrara, Italy 2AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK (Requests for offprints should be addressed to H E Jones; Email: joneshe1@cardiff.ac.uk) 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 mM 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)d, (b) an increased sensitivity to growth