HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter-Mediated Chemoresistance in Small Cell Lung Cancer
HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter-Mediated Chemoresistance in Small Cell Lung Cancer
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DOI：
10.1158/1535-7163.mct-11-0884
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发表时间：
2012-04-01
影响因子：
5.7
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
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作者：
Minami, Toshiyuki;Kijima, Takashi;Kumanogoh, Atsushi
小细胞肺癌（SCLC）在成功的初始治疗后很容易获得多重耐药性。 ATP 结合盒 (ABC) 转运蛋白的过度表达对于多药耐药性非常重要。其中，ABCB1 和 ABCG2 已知在化疗耐药 SCLC 细胞中表达上调。我们发现，与化疗敏感的 SBC-3 细胞相比，化疗耐药的 SBC-3/ETP、SBC-3/SN-38 和 SBC-3/CDDP 细胞中人表皮生长因子受体 2 (HER2) 的表达也上调。拉帕替尼是一种 HER2 酪氨酸激酶抑制剂，无法单独抑制这些 HER2 阳性 SCLC 细胞的增殖，但成功恢复了临床适用浓度的依托泊苷和 SN-38 的化疗敏感性。拉帕替尼的逆转作用被认为是由 ABC 转运蛋白的药物外排泵功能的抑制引起的，尽管据报道拉帕替尼本身是它们的底物。此外，通过短干扰RNA敲低HER2削弱了拉帕替尼对ABCB1的作用，表明HER2参与了抑制机制。值得注意的是，我们发现 Caveolin-1 和 Src 在通过 HER2 失活调节 ABCB1 功能中发挥关键作用。在 SBC-3/ETP 细胞中，拉帕替尼对 HER2 的去磷酸化会激活 Src，并依次导致 Caveolin-1 磷酸化增加。通过这个过程，caveolin-1与HER2解离并加强与ABCB1的结合，最终损害泵功能。此外，我们发现拉帕替尼与依托泊苷或伊立替康联合治疗分别显着抑制小鼠皮下 SBC-3/ETP 和 SBC-3/SN-38 肿瘤的生长。总的来说，这些结果表明拉帕替尼和细胞毒药物的联合治疗可以克服 ABC 转运蛋白介导的化疗耐药性，尤其是在 HER2 阳性 SCLC 中。摩尔癌症治疗； 11(4)； 830-41。 (C) 2012 年 AACR。
Small cell lung cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC cells. We found that human epidermal growth factor receptor 2 (HER2) expressions are also upregulated in chemoresistant SBC-3/ETP, SBC-3/SN-38, and SBC-3/CDDP cells, compared with chemosensitive SBC-3 cells. Lapatinib, a tyrosine kinase inhibitor of HER2, could not suppress proliferation of these HER2-positive SCLC cells alone but successfully restored chemosensitivity to etoposide and SN-38 with a clinically applicable concentration. The reversal effect of lapatinib was thought to be caused by inhibition of drug efflux pump functions of ABC transporters, although lapatinib itself has been reported to be a substrate for them. Moreover, knocking down of HER2 by an short interfering RNA weakened the effect of lapatinib on ABCB1, indicating the involvement of HER2 in the inhibitory mechanisms. Notably, we showed that caveolin-1 and Src play key roles in modulating ABCB1 function via HER2 inactivation. In SBC-3/ETP cells, dephosphorylation of HER2 by lapatinib activates Src and successively leads to increased caveolin-1 phosphorylation. Through this process, caveolin-1 dissociates from HER2 and strengthens association with ABCB1, and finally impairs the pump functions. Furthermore, we showed that treatment by lapatinib in combination with etoposide or irinotecan significantly suppresses the growth of subcutaneous SBC-3/ETP and SBC-3/SN-38 tumors in mice, respectively. Collectively, these results indicate that combination therapy with lapatinib and cytotoxic agents could conquer ABC transporter-mediated chemoresistance especially in HER2-positive SCLC. Mol Cancer Ther; 11(4); 830-41. (C) 2012 AACR.