Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways
Siyuan Zhang1, Wen-Chien Huang, Ping Li
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Nature Medicine
|March 15, 2011
Summary
Trastuzumab resistance in ERBB2-positive breast cancer is linked to activated c-SRC (SRC). Targeting SRC with trastuzumab overcomes resistance and eliminates tumors, offering a new clinical strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapy
Background:
- Trastuzumab is an ERBB2-targeted therapy for breast cancer.
- Many patients develop resistance to trastuzumab due to various mechanisms.
- Effective treatments to overcome trastuzumab resistance are needed.
Purpose of the Study:
- To identify key modulators of trastuzumab resistance.
- To investigate the role of c-SRC (SRC) in trastuzumab resistance pathways.
- To evaluate SRC inhibition as a strategy to overcome trastuzumab resistance.
Main Methods:
- Analysis of SRC activation in trastuzumab-resistant breast cancer cells (acquired and de novo).
- Investigation of SRC regulation by PTEN.
- In vitro and in vivo studies combining SRC inhibitors with trastuzumab.
Main Results:
- SRC is activated in trastuzumab-resistant cells and is a common node in resistance pathways.
- A novel PTEN-mediated dephosphorylation mechanism regulates SRC.
- Combined SRC and trastuzumab therapy sensitized resistant cells and eradicated tumors in vivo.
Conclusions:
- SRC activation is a critical factor in trastuzumab resistance.
- Targeting SRC in combination with trastuzumab is a promising strategy to overcome resistance in ERBB2-positive breast cancer.
- This approach has potential clinical applications for resistant breast cancer patients.
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