Different mechanisms for resistance to trastuzumab versus lapatinib in her2- positive breast cancers - role of estrogen receptor and her2 reactivation
| Autor: | Gladys Morrison, Rachel Schiff, Yen-Chao Wang, C. Kent Osborne, Ryan M. Gillihan, Xiaoyong Fu, Maria F. Botero, N.A. Healy, Jun Guo, Robin Ward, Mothaffar F. Rimawi, Gail Lewis Phillips, Susan G. Hilsenbeck, Gary C. Chamness |
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| Rok vydání: | 2011 |
| Předmět: |
Receptor
ErbB-3 Receptor ErbB-2 Gene Expression Estrogen receptor Pharmacology growth-factor receptor Tyrosine-kinase inhibitor Mice 0302 clinical medicine tyrosine kinase inhibitor Trastuzumab antibody Receptor skin and connective tissue diseases Medicine(all) 0303 health sciences gw572016 plus targeted therapy 3. Good health adjuvant chemotherapy Receptors Estrogen 030220 oncology & carcinogenesis Female Research Article medicine.drug medicine.drug_class Mice Nude Antineoplastic Agents Breast Neoplasms Antibodies Monoclonal Humanized Lapatinib 03 medical and health sciences Growth factor receptor Cell Line Tumor expression medicine Animals Humans neoplasms Cell Proliferation 030304 developmental biology Fulvestrant Cell growth business.industry Xenograft Model Antitumor Assays Drug Resistance Neoplasm Quinazolines cells activation business |
| Zdroj: | Breast Cancer Research : BCR |
| Popis: | Introduction: The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs. Methods: Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts. Results: ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L-and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts. Conclusions: Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients. |
| Databáze: | OpenAIRE |
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