Abstract 1824: Mechanisms of resistance to anti-EGFR/HER2 therapy in breast cancer

Therapy resistance to epidermal growth factor receptor family (EGFR and HER2) targeted therapies has been an obstacle for treatment success in breast cancer. Therefore, our goal is to investigate the mechanisms of resistance to these therapeutics and look for alternative ways to overcome such resistance. We previously created and characterized syngeneic gefitinib and lapatinib (EGFR and HER2 therapeutics) therapy resistant variants of the therapy sensitive SKBR3 human breast cancer cell line. We found that key mechanisms of resistance involved downregulation of miR-200a and upregulation of miR-221/222 families, which are known to regulate epithelial to mesenchymal transition (EMT). To validate the role of miR-221/222 in therapy resistance, western blots were performed for the miR-221/222 target Trichorhinophalangeal syndrome type I (TRPS1) protein. Downregulation of TRPS1 is known to promote EMT and metastasis. As expected, our results showed a downregulation of TRPS1 in the therapy resistant cells compare to the therapy sensitive cells. Since miR-200a was significantly downregulated in the therapy resistant cells, we ectopically expressed miR-200a in the EGFR therapy resistant SKBR3 cells using a lentiviral vector. MiR-200a expressing cells were selected by puromycin resistance. Preliminary data showed a decrease in the fold resistance of cells resistant to lapatinib transfected with lentiviral vector overexpressing miR-200a. These results suggest that overexpression of miR-200a in lapatinib resistant cells can be used to overcome therapy resistance in breast cancer. Citation Format: Luis Daniel Borrero-Garcia, Brian Vidal, Suranganie Dharmawardhane. Mechanisms of resistance to anti-EGFR/HER2 therapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1824.