AZD3409 inhibits the growth of breast cancer cells with intrinsic resistance to the EGFR tyrosine kinase inhibitor gefitinib
- 27 September 2006
- journal article
- Published by Springer Science and Business Media LLC in Breast Cancer Research and Treatment
- Vol. 102 (3), 275-282
- https://doi.org/10.1007/s10549-006-9340-7
Abstract
AKT and MAPK signaling are involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. RAS proteins are upstream mediators that transfer messages from surface receptors to intracellular signal transducers including MAPK and AKT pathways. AZD3409 is a novel prenyl inhibitor that has shown activity against both farnesyl transferase and geranylgeranyl transferase in isolated enzyme studies. We explored the activity of AZD3409 on breast cancer cell lines with high (SK-Br-3), intermediate (MDA-MB-361) or low (MDA-MB-468) sensitivity to gefitinib. We found that AZD3409 inhibits the growth of breast cancer cells in a dose-dependent manner, with the MDA-MB-468 and MDA-MB-361 cell lines showing higher sensitivity as compared with SK-Br-3 cells. Treatment with AZD3409 produced a significant reduction in the levels of activation of AKT in the three cell lines. AZD3409 also induced an increase in the expression of p27kip-1 and of hypophosphorylated forms of pRb2 in MDA-MB-468 cells that was associated with accumulation of cells in G0/G1 and the appearance of a sub-G1 peak suggestive of apoptosis. In contrast, AZD3409 produced a G2 arrest associated with reduced expression of pRb2 in MDA-MB-361 cells. A synergistic anti-tumor effect was observed when MDA-MB-468 or MDA-MB-361 cells were treated with both AZD3409 and gefitinib, whereas this combination was only additive in SK-Br-3 cells. However, treatment of breast cancer cells with AZD3409 and gefitinib did not produce a more significant blockade of AKT signaling as compared with gefitinib alone. These data suggest that AZD3409 might be active in gefitinib-resistant breast carcinoma.This publication has 28 references indexed in Scilit:
- Development of Farnesyl Transferase Inhibitors: A ReviewThe Oncologist, 2005
- Overview of tyrosine kinase inhibitors in clinical breast cancerEndocrine-Related Cancer, 2005
- Farnesyltransferase Inhibitor, ABT-100, Is a Potent Liver Cancer Chemopreventive AgentClinical Cancer Research, 2005
- The farnesyl transferase inhibitor R115777 (Zarnestra®) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa®) and PamidronateOncogene, 2004
- Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (‘Iressa’) is independent of EGFR expression levelJournal of Cellular Physiology, 2003
- Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitorsOncogene, 2003
- The Farnesyl Transferase Inhibitor SCH 66336 Induces a G2 → M or G1 Pause in Sensitive Human Tumor Cell LinesExperimental Cell Research, 2001
- Aberrant function of the Ras signal transduction pathway in human breast cancerBreast Cancer Research and Treatment, 1995
- ras GENESAnnual Review of Biochemistry, 1987
- Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitorsAdvances in Enzyme Regulation, 1984