期刊
ONCOTARGET
卷 7, 期 10, 页码 11539-11552出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7317
关键词
resistance; breast cancer; EMT; HER2; proteomics
资金
- Cancer Research UK [C157/A15703, C6088/A12063]
- Wellcome Trust Institutional Strategic Support Fund
- Wellcome Trust Strategic Award
- Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council [BB/D019621/1]
- BBSRC [BB/D019621/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D019621/1] Funding Source: researchfish
- Medical Research Council [1201653, 1584339, 1584178] Funding Source: researchfish
Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in the treatment of HER2-positive breast cancer is a major clinical problem. To identify pathways linked to resistance, we generated HER2-positive breast cancer cell lines which are resistant to either lapatinib or AZD8931, two pan-HER family kinase inhibitors. Resistance was HER2 independent and was associated with epithelial-to-mesenchymal transition (EMT), resulting in increased proliferation and migration of the resistant cells. Using a global proteomics approach, we identified a novel set of EMT-associated proteins linked to HER2-independent resistance. We demonstrate that a subset of these EMT-associated genes is predictive of prognosis within the ERBB2 subtype of human breast cancers. Furthermore, targeting the EMT-associated kinases Src and Axl potently inhibited proliferation of the resistant cells, and inhibitors to these kinases may provide additional options for the treatment of HER2-independent resistance in tumors.
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