Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells
Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells
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DOI：
10.1158/1535-7163.mct-07-2068
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发表时间：
2008-03-01
影响因子：
5.7
通讯作者：
Kim, Tae-You
中科院分区：
文献类型：
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作者：
Kim, Hwang-Phill;Han, Sae-Won;Kim, Tae-You
尽管在其表皮生长因子受体（EGFR）中具有体细胞突变的非小细胞肺癌（NSCLC）细胞最初显示出对酪氨酸激酶抑制剂（TKI）的显著应答，但这些细胞最终发展出对TKI的抗性。这种耐药性可能是由EGFR酪氨酸激酶中的继发性T790M突变引起的，该突变导致790中的甲硫氨酸或苏氨酸被取代。在这项研究中，我们发现拉帕替尼和西妥昔单抗的组合克服了T790M突变NSCLC的吉非替尼耐药。观察到T790M肺癌细胞对吉非替尼耐药，耐药细胞中Stat3持续激活。一种可逆的EGFR和HER2 TKI拉帕替尼通过阻断EGFR和HER2的异源二聚化降低了Stat3的激活，这导致对吉非替尼耐药T790 M细胞的抑制作用适度增加。除拉帕替尼外，抗EGFR抗体西妥昔单抗也可诱导T790 M细胞中EGFR下调和细胞凋亡。最后，拉帕替尼和西妥昔单抗联合治疗导致体外和体内对吉非替尼耐药T790M细胞的细胞毒性显著增强。总之，这些数据表明，拉帕替尼和西妥昔单抗联合治疗（诱导二聚体解离和EGFR下调）似乎是治疗EGFR TKI耐药NSCLC患者的有效策略。
Although non-small cell lung cancer (NSCLC) cells with somatic mutations in their epidermal growth factor receptors (EGFR) initially show a dramatic response to tyrosine kinase inhibitor (TKI), these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine or threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. e observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC.