Heat shock factor 1 confers resistance to lapatinib in ERBB2-positive breast cancer cells
| Autor: | Natalia D. Marchenko, Lucas Garcia, Alisha R. Yallowitz, Evguenia M. Alexandrova, Amr M. Ghaleb |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Receptor ErbB-2 Immunology Breast Neoplasms Lapatinib Receptor tyrosine kinase Article 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Heat Shock Transcription Factors In vivo Heat shock protein Cell Line Tumor medicine Animals Humans Kinome HSP90 Heat-Shock Proteins Heat shock lcsh:QH573-671 HSF1 skin and connective tissue diseases Cell Proliferation biology lcsh:Cytology Cell Biology Hsp90 Mice Inbred C57BL 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Proteolysis biology.protein Cancer research Female Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | Cell Death and Disease, Vol 9, Iss 6, Pp 1-13 (2018) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Despite success of ERBB2-targeted therapies such as lapatinib, resistance remains a major clinical concern. Multiple compensatory receptor tyrosine kinase (RTK) pathways are known to contribute to lapatinib resistance. The heterogeneity of these adaptive responses is a significant hurdle for finding most effective combinatorial treatments. The goal of this study was to identify a unifying molecular mechanism whose targeting could help prevent and/or overcome lapatinib resistance. Using the MMTV-ERBB2;mutant p53 (R175H) in vivo mouse model of ERBB2-positive breast cancer, together with mouse and human cell lines, we compared lapatinib-resistant vs. lapatinib-sensitive tumor cells biochemically and by kinome arrays and evaluated their viability in response to a variety of compounds affecting heat shock response. We found that multiple adaptive RTKs are activated in lapatinib-resistant cells in vivo, some of which have been previously described (Axl, MET) and some were novel (PDGFRα, PDGFRβ, VEGFR1, MUSK, NFGR). Strikingly, all lapatinib-resistant cells show chronically activated HSF1 and its transcriptional targets, heat shock proteins (HSPs), and, as a result, superior tolerance to proteotoxic stress. Importantly, lapatinib-resistant tumors and cells retained sensitivity to Hsp90 and HSF1 inhibitors, both in vitro and in vivo, thus providing a unifying and actionable therapeutic node. Indeed, HSF1 inhibition simultaneously downregulated ERBB2, adaptive RTKs and mutant p53, and its combination with lapatinib prevented development of lapatinib resistance in vitro. Thus, the kinome adaptation in lapatinib-resistant ERBB2-positive breast cancer cells is governed, at least in part, by HSF1-mediated heat shock pathway, providing a novel potential intervention strategy to combat resistance. |
| Databáze: | OpenAIRE |
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