Department of Cancer and Cell Biology, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA.
Anticancer Res. 2011 Mar;31(3):789-95.
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.
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.
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.
双激酶抑制剂拉帕替尼（泰克布）已被应用于晚期乳腺癌。然而，其在临床上的疗效并不明显，需要开发新的方法来增强其反应性。在这项研究中，我们测试了非受体酪氨酸激酶 c-Abl 是否调节乳腺癌细胞对拉帕替尼的反应性，如果是这样，那么用拉帕替尼联合 c-ABL 激酶抑制剂伊马替尼（STI571；格列卫）治疗是否可以使乳腺癌细胞对治疗更敏感。
通过 RNA 干扰沉默内源性 c-ABL 激酶或用伊马替尼抑制 c-ABL 激酶，以测量细胞生长和细胞周期进程，来测试联合治疗是否能改善拉帕替尼耐药的乳腺癌细胞系 MDA-MB-468 和 T47D 的反应性。
通过靶向 c-ABL 的功能可以提高对拉帕替尼的反应性，这表明拉帕替尼联合伊马替尼的联合治疗可能会带来显著的治疗获益。
