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Insulin-like growth factor-1 receptor signalling and acquired resistance to gefitinib (ZD1839; IRESSATM) in DU145 human prostate cancer cells

By Helen E. Jones, Lindy Goddard, Julia M.W. Gee, Stephen Hiscox, Maureen E. Harper, Michele Rubini, Denise Barrow, Simon Guy, Alan Wakeling and Robert I. Nicholson


Introduction: Although gefitinib (ZD1839; IRESSATM), a specific EGF-R tyrosine kinase inhibitor (TKI), has been shown to possess anti-tumour activity in a range of cancer types including androgen refractory prostate cancer, de novo and acquired resistance to the inhibitor has been reported clinically (Ranson, The Oncologist 2001; 58 (suppl 2A):114-22). In this study, we examined the involvement of the IGF1-R in the acquisition of resistance to gefitinib in the DU145 model of prostate cancer. Methods: The DU145 human prostate cancer cell line was continuously exposed to 1mM gefitinib. Alterations in signalling pathways were assessed using immunocytochemical, Western blotting and/or RTPCR techniques. Matrigel invasion assays were performed and cell proliferation was assessed by evaluating anchorage dependent growth. Cell sensitivity to the specific IGF1-R TKI, AG1024, (1-10mg/ml) was also measured. Results: Continuous exposure of the DU145 cells to 1mM gefitinib resulted in an approximate 60% initial growth inhibition after 10 days treatment. The surviving cells however, showed slow but steady increases in growth over the following 2 months, reaching a stable growth rate which far exceeded that of the parental cell line after a total of 3 months. This gefitinib-resistant subline designated DU145/TKI-R, demonstrated reduced EGF-R expression and negligible basal phosphorylated EGF-R activity. Compared with the parental DU145 cells, the DU145/TKI-R cells showed i) an increased production of IGFII mRNA, ii) elevated levels of both total and phosphorylated IGF1-R and PKCd, and iii) a marked increased sensitivity to growth inhibition by the IGF1-R inhibitor AG1024. Significantly, while 1mM gefitinib initially reduced the invasion of the DU145 cells through matrigel by 40%, the DU145/TKI-R cells overcame this inhibition. Furthermore, the migratory activity of the DU145/TKI-R cells was substantially reduced (45%) by treatment with AG1024 (10mM).\ud Conclusion: In prostate cancer cells, acquired resistance to gefitinib is associated with increased signalling through the IGF1-R, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype. Thus, therapeutic strategies that target the IGF1-R may increase the efficacy and duration of response to gefitinib

Year: 2003
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