Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling
Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling
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DOI：
10.1158/1535-7163.mct-06-0423
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发表时间：
2007-02-01
影响因子：
5.7
通讯作者：
Esteva, Francisco J.
中科院分区：
文献类型：
--
作者：
Nahta, Rita;Yuan, Linda X. H.;Esteva, Francisco J.
大多数对HER2靶向抗体曲妥珠单抗有初步治疗反应的乳腺癌患者将在1年内出现疾病进展。因此，识别有效抑制曲妥珠单抗进展的癌细胞存活的新药物是至关重要的。在目前的研究中，我们发现双重表皮生长因子受体(EGFR)/人EGFR-2(HER2)激酶抑制剂拉帕替尼诱导曲妥珠单抗耐药细胞凋亡，该细胞来自HER2过表达的SKBR3乳腺癌株。拉帕替尼抑制耐药细胞中的EGFR和HER2信号转导，阻断Akt下游、丝裂原活化蛋白激酶和S6激酶的激活，并诱导p27kip1的表达。重要的是，拉帕替尼还抑制亲本细胞和耐药细胞中的胰岛素样生长因子I(IGF-I)信号转导和促生长作用，而IGF-I受体阻断抗体αIR3进一步增强了拉帕替尼的细胞毒作用。随着IGF-I受体信号的增加与曲妥珠单抗耐药有关，我们的数据有力地支持了进一步研究拉帕替尼作为曲妥珠单抗治疗乳腺癌的潜在疗法。
The majority of breast cancer patients who achieve an initial therapeutic response to the HER2-targeted antibody trastuzumab will show disease progression within 1 year. Thus, the identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical. In the current study, we show that the dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) kinase inhibitor lapatinib induces apoptosis in trastuzumab-resistant cells derived from the HER2-overexpressing SKBR3 breast cancer line. Lapatinib inhibited EGFR and HER2 signaling in resistant cells, blocking activation of downstream Akt, mitogen-activated protein kinase, and S6 kinases and inducing expression of p27kip1. Importantly, lapatinib also inhibited insulin-like growth factor I (IGF-I) signaling and growth-promoting effects in parental and resistant cells, and the cytotoxic effects of lapatinib were further enhanced by the IGF-I receptor-blocking antibody alpha IR3. As increased IGF-I receptor signaling has been implicated in trastuzumab resistance, our data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab.