Researchers have identified a protein that may play a critical role in preventing some tumor cells from responding to the breast cancer drug trastuzumab (Herceptin). The researchers also showed, in preclinical experiments, that it may be possible to overcome this resistance by combining trastuzumab with a drug to inhibit the protein, c-SRC. The findings appeared online in Nature Medicine on March 13.
Multiple mechanisms of resistance associated with trastuzumab have been identified, but there are no effective methods for overcoming this resistance. To address this problem, Dr. Dihua Yu, an NCI-supported investigator from the University of Texas M. D. Anderson Cancer Center, and her colleagues studied signaling pathways that are activated in resistant cancer cells. They found that cellular signals from multiple resistance pathways converged at c-SRC, which is known to play a role in some cancers.
When activated, c-SRC may be a critical component of multiple resistance pathways. Rather than targeting several different signaling pathways individually in resistant cells, it may be possible to inhibit a central component common to all these pathways to overcome resistance, the researchers suggested.
To test this idea, resistant cells were exposed to a combination of trastuzumab plus a c-SRC inhibitor called saracatinib. In the cells and animal models, this combination of drugs made resistant cells more sensitive to trastuzumab, and tumors shrank. Using data from women treated with trastuzumab, the researchers were also able to confirm the potential role of c-SRC activation in trastuzumab resistance in patients.
“By targeting c-SRC, we reversed its activation in several model systems,” said Dr. Yu. “We consider this to be a powerful strategy for overcoming resistance.” The next steps would be to evaluate clinically applicable c-SRC inhibitors, including dasatinib, and develop a clinical trial to test the approach in patients, she noted.
Also in the Journals: New Clue to Triple-Negative Breast Cancer
A protein that normally helps suppress cell proliferation and tumor formation is mutated or missing in some cases of triple-negative breast cancer, and these alterations may play a role in the development of this disease. The discovery, reported in the March 4 Cell, provides new insights into this aggressive form of breast cancer, which is both poorly understood and difficult to treat.
In normal cells, the protein PTPN12 appears to block growth-promoting signals from proteins called tyrosine kinases. But, in triple-negative breast cancer, PTPN12 activity may be lost. Without this protein acting as a tumor suppressor, cells may produce a range of abnormal growth signals, the researchers found.
The results suggest that it may be possible to treat some triple-negative breast cancers with combinations of available drugs called tyrosine kinase inhibitors.
full-text:
NCI Cancer Bulletin for March 22, 2011 - National Cancer Institute
triple-negative breast cancer (TRIH-pul-NEH-guh-tiv brest KAN-ser)
Describes breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein. Also called ER-negative PR-negative HER2/neu-negative and ER-PR-HER2/neu-.
tyrosine kinase inhibitor (TY-ruh-seen KY-nays in-HIH-bih-ter)
A drug that interferes with cell communication and growth and may prevent tumor growth. Some tyrosine kinase inhibitors are used to treat cancer.
signaling pathway (SIG-nuh-ling …)
Describes a group of molecules in a cell that work together to control one or more cell functions, such as cell division or cell death. After the first molecule in a pathway receives a signal, it activates another molecule. This process is repeated until the last molecule is activated and the cell function involved is carried out. Abnormal activation of signaling pathways can lead to cancer, and drugs are being developed to block these pathways. This may help block cancer cell growth and kill cancer cells.
saracatinib
An orally available 5-, 7-substituted anilinoquinazoline with anti-invasive and anti-tumor activities. Saracatinib is a dual-specific inhibitor of Src and Abl, protein tyrosine kinases that are overexpressed in chronic myeloid leukemia cells. This agent binds to and inhibits these tyrosine kinases and their effects on cell motility, cell migration, adhesion, invasion, proliferation, differentiation, and survival. Specifically, saracatinib inhibits Src kinase-mediated osteoclast bone resorption. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)
Code name: AZD0530
Chemical structures: 4-Quinazolinamine, N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methyl-1- piperazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-
N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-[(tetrahydro- 2H-pyran-4-yl)oxy]quinazolin-4-amine
Definition of saracatinib - National Cancer Institute Drug Dictionary - National Cancer Institute
Combating trastuzumab resistance by targeting SRC,... [Nat Med. 2011] - PubMed result
Combating trastuzumab resistance by targeting SRC,... [Nat Med. 2011] - PubMed result
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