June 25, 2008 Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer. However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug.
New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown. As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.
The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R. This meant that two proteins known as IRS-1 and PI3K were always associated. If this association was disrupted then the cells once again became susceptible to the effects of gefitinib.
Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence.
The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.
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- Guix et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI34588
- Wang et al. Mechanisms of resistance to ErbB-targeted cancer therapeutics. Journal of Clinical Investigation, 2008; DOI: 10.1172/JCI36260
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