Inhibition of c-ABL sensitizes breast cancer cells to the dual ErbB receptor tyrosine kinase inhibitor lapatinib (GW572016).

摘要

BACKGROUND: The dual kinase inhibitor lapatinib (Tykerb) has been applied for advanced breast cancer. However, the effectiveness in the clinic has been elusive and the development of novel approaches to enhance the responsiveness is needed. In this study, we test whether the non-receptor tyrosine kinase c-Abl regulates the responsiveness of breast cancer cells to lapatinib and, if so, whether the combination treatment with lapatinib plus the c-ABL kinase inhibitor imatinib (STI571; Gleevec) can sensitize breast cancer cells to the treatment. MATERIALS AND METHODS: The endogenous c-ABL kinase was silenced by RNA interference or inhibited by imatinib to test whether the co-treatment improves the responsiveness of the lapatinib-resistant breast cancer cell lines MDA-MB-468 and T47D, by measuring cell growth and cell-cycle progression. CONCLUSION: The responsiveness to lapatinib can be improved by targeting the function of c-ABL, suggesting that combination treatment of lapatinib plus imatinib can lead to significant gains in therapeutic benefit.