11/15/2022 0 Comments Bt-474 clone 5 kadcylaThe Human Epidermal Growth Factor Receptor (HER) family is a well characterised group of membrane-bound receptor tyrosine kinases (RTKs) which consists of four closely related members: EGFR (HER1), HER2, HER3 and HER4 6, 7, 8. These in turn underline the need for further research to develop a better understanding of the mechanisms of resistance to therapy and for development of more effective therapeutic and less toxic approaches for the management of breast cancer 3, 4, 5. Major challenges in breast cancer management are primary or acquired resistance to current therapies. Breast cancer also has the highest mortality of any cancer in women worldwide 1 and the second highest in the United Kingdom 2. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.ĭespite significant advances in diagnosis and treatment in recent years, breast cancer is still the most commonly diagnosed cancer among women worldwide, with over 1.6 million cases (accounting for 25% of all cancers) diagnosed in 2012 1. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Overexpression of HER2 has been reported in around 25% of human breast cancers.
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