Duke University Medical Center, Hock Plaza, Suite 601, 2424 Erwin Road, Durham, NC 27710, USA.
Mol Cancer Ther. 2010 Feb;9(2):292-9. doi: 10.1158/1535-7163.MCT-09-1041. Epub 2010 Feb 2.
The widespread clinical use of therapies targeting the ErbB2 receptor tyrosine kinase oncogene represents a significant advance in breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that lapatinib (GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2(+) breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2(+) breast cancer cell lines, which was mediated by the calcium-dependent activation of RelA, the prosurvival subunit of NF-kappaB. Abrogation of lapatinib-induced RelA activation using either small interfering RNA constructs or an intracellular calcium chelator enhanced the apoptotic effects of lapatinib in parental ErbB2(+) breast cancer cells and overcame therapeutic resistance to lapatinib in ErbB2(+) breast cancer lines that had been rendered resistant to lapatinib through chronic exposure to the drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2(+) breast cancers treated with lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by lapatinib in ErbB2(+) breast cancers, and showing its role in the development of therapeutic resistance to lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to lapatinib in some women with ErbB2(+) breast cancers.
针对 ErbB2 受体酪氨酸激酶致癌基因的治疗方法在临床上的广泛应用是乳腺癌治疗的重大进展。然而，治疗耐药性的发展是限制其临床疗效的一个难题，特别是那些阻断 ErbB2 自身磷酸化和激活的小分子酪氨酸激酶抑制剂。在这里，我们发现 lapatinib（GW572016），一种高度选择性的 ErbB2 和表皮生长因子受体酪氨酸激酶小分子抑制剂，最近被批准用于治疗晚期 ErbB2（+）乳腺癌，它出人意料地在 ErbB2（+）乳腺癌细胞系中引发了一种细胞保护应激反应，这种反应是由钙依赖性激活 RelA 介导的，RelA 是 NF-κB 的生存亚单位。使用小干扰 RNA 构建体或细胞内钙螯合剂阻断 lapatinib 诱导的 RelA 激活，增强了 lapatinib 在亲本 ErbB2（+）乳腺癌细胞中的凋亡作用，并克服了通过慢性暴露于药物而对 lapatinib 产生耐药性的 ErbB2（+）乳腺癌系对 lapatinib 的治疗耐药性，模拟了临床环境。此外，对接受 lapatinib 单药治疗的 ErbB2（+）乳腺癌患者的连续临床活检中磷酸化 RelA 表达的变化进行分析，发现在应答者和无应答者之间存在统计学上的显著差异，这与我们的临床前发现一致。阐明 lapatinib 在 ErbB2（+）乳腺癌中对 RelA 的调节作用，并显示其在 lapatinib 治疗耐药性发展中的作用，为克服或预防某些 ErbB2（+）乳腺癌患者对 lapatinib 耐药性的发生提供了另一个治疗靶点。
