Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression

Abstract To investigate the potential value of targeting insulin-like growth factor-1 receptor (IGF-1R) in breast cancer, we examined the effects of NVP-AEW541, a selective small-molecule inhibitor of the IGF-1R tyrosine kinase, in a panel of 16 breast cancer cell lines. All cell lines expressed IGF...

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Published in:	Cancer letters Vol. 282; no. 1; pp. 14 - 24
Main Authors:	Mukohara, Toru, Shimada, Hiroyuki, Ogasawara, Naomi, Wanikawa, Ryoko, Shimomura, Manami, Nakatsura, Tetsuya, Ishii, Genichiro, Park, Joon Oh, Jänne, Pasi A, Saijo, Nagahiro, Minami, Hironobu
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 08-09-2009 Elsevier Limited
Subjects:	Antineoplastic Agents - therapeutic use Blotting, Western Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cell Division - drug effects Cell growth Cell Line, Tumor Enzyme Inhibitors - therapeutic use Hematology, Oncology and Palliative Medicine Humans IGF-1R Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin-like growth factors IRS-1 Kinases Medical research Phosphorylation Protein-Tyrosine Kinases - antagonists & inhibitors Pyrimidines - therapeutic use Pyrroles - therapeutic use Receptor Protein-Tyrosine Kinases - drug effects Receptor Protein-Tyrosine Kinases - metabolism Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Tyrosine kinase inhibitor Breast cancer IGF-1R IRS-1 Tyrosine kinase inhibitor
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Summary:	Abstract To investigate the potential value of targeting insulin-like growth factor-1 receptor (IGF-1R) in breast cancer, we examined the effects of NVP-AEW541, a selective small-molecule inhibitor of the IGF-1R tyrosine kinase, in a panel of 16 breast cancer cell lines. All cell lines expressed IGF-1R, but MCF-7 expressed much higher levels of insulin receptor substrate-1 (IRS-1) than the others. NVP-AEW541 was more potent at inhibiting growth of MCF-7 cells as compared to the others (IC50 , 1 μM vs. ≈7 μM). Comparing MCF-7 to T47D cells, which express IGF-1R at a level identical to MCF-7 but have less than 1/30 the amount of IRS-1, NVP-AEW541 caused cell-cycle arrest at the G1–S boundary, reduced in vitro cell migration, and enhanced the cytotoxic effects of vinorelbine and paclitaxel in MCF-7, but not in T47D. While NVP-AEW541 decreased the phosphorylation of IGF-1R in both cell lines, it inhibited phosphorylation of Akt and disrupted the IRS-1/PI3 K complex only in MCF-7. These findings suggest that inhibiting IGF-1R may be an effective therapeutic strategy for breast cancers that co-express IGF-1R and IRS-1 at high levels.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0304-3835 1872-7980
DOI:	10.1016/j.canlet.2009.02.056