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Article

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line

1
Division of Oncology/Hematology, Department of Internal Medicine, Korea University College Medicine, Seoul 02841, Korea
2
Departments of Breast and Endocrine surgery, Korea University College Medicine, Seoul 02841, Korea
3
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02456, Korea
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2630; https://doi.org/10.3390/cancers12092630
Received: 7 August 2020 / Revised: 11 September 2020 / Accepted: 12 September 2020 / Published: 15 September 2020
Lapatinib is a tyrosine kinase inhibitor widely used as a treatment for a Human Epidermal growth factor Receptor 2 (HER2) (+) breast cancer patients. However, when resistance is acquired through continued exposure, and it is associated with a poor prognosis for patients. In this study, we identified HSP90 as a common node for acquired resistance to lapatinib in two lapatinib resistant cell lines using proteomic analysis. Notably, in vitro and in vivo studies demonstrated synergy effect between lapatinib and an HSP90 inhibitor were observed in the estrogen receptor (+) HER2 (+) breast cancer cell only. These results could be a potential strategy for future clinical trials for HSP90 inhibitors in treatment—refractory HER2 (+) metastatic cancer patients
Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials. View Full-Text
Keywords: breast cancer; ER (+) HER2 (+); lapatinib resistance; HSP90 breast cancer; ER (+) HER2 (+); lapatinib resistance; HSP90
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MDPI and ACS Style

Lee, H.J.; Shin, S.; Kang, J.; Han, K.-C.; Kim, Y.H.; Bae, J.-W.; Park, K.H. HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line. Cancers 2020, 12, 2630. https://doi.org/10.3390/cancers12092630

AMA Style

Lee HJ, Shin S, Kang J, Han K-C, Kim YH, Bae J-W, Park KH. HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line. Cancers. 2020; 12(9):2630. https://doi.org/10.3390/cancers12092630

Chicago/Turabian Style

Lee, Hye J., Seungho Shin, Jinho Kang, Ki-Cheol Han, Yeul H. Kim, Jeoung-Won Bae, and Kyong H. Park 2020. "HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line" Cancers 12, no. 9: 2630. https://doi.org/10.3390/cancers12092630

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