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-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 (IC(50), 1 microM vs. approximately 7 microM). 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/PI3K 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.

• Authors: Toru Mukohara, Hiroyuki Shimada, Naomi Ogasawara, Ryoko Wanikawa, Manami Shimomura, Tetsuya Nakatsura, Genichiro Ishii, Joon Oh Park, Pasi A Jänne, Nagahiro Saijo, Hironobu Minami
• Journal: Cancer letters (Cancer Lett) Vol. 282 Issue 1 Pg. 14-24 (Sep 08 2009) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 19345478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• NVP-AEW541
• Pyrimidines
• Pyrroles
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• Receptor, IGF Type 1

Topics

• Antineoplastic Agents (therapeutic use)
• Blotting, Western
• Breast Neoplasms (drug therapy, pathology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Enzyme Inhibitors (therapeutic use)
• Humans
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Phosphorylation
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrimidines (therapeutic use)
• Pyrroles (therapeutic use)
• Receptor Protein-Tyrosine Kinases (drug effects, metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)