HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells.
HER2 oncogenic function escapes EGFR tyrosine kinase inhibitors via activation of alternative HER receptors in breast cancer cells.
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DOI：
10.1371/journal.pone.0002881
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发表时间：
2008-08-06
期刊：
影响因子：
3.7
通讯作者：
Larijani B
中科院分区：
文献类型：
--
作者：
Kong A;Calleja V;Leboucher P;Harris A;Parker PJ;Larijani B
癌症患者对 EGFR 酪氨酸激酶抑制剂 (TKI) 的反应率可能较差且不可预测，因为 EGFR 表达本身是一个不充分的反应指标。人们对这种耐药性背后的机制了解有限。此外，尽管 TKI 可以抑制 HER2 过度表达的乳腺肿瘤细胞的生长，但在生理剂量下它们并不能完全抑制 HER2 致癌功能。在这里，我们提供了一种分子机制，说明 HER2 致癌功能如何通过自分泌配体释放导致的替代 HER 受体激活来逃避 TKI 的抑制。使用监测原位 HER 受体磷酸化的福斯特共振能量转移 (FRET) 以及经典生化分析，我们发现 EGFR、AG1478 和易瑞沙（吉非替尼）的特异性酪氨酸激酶抑制剂 (TKI) 通过抑制 EGFR/HER3 二聚化来降低 EGFR 和 HER3 磷酸化。因此，我们证明 HER4 的裂解和 HER4/HER2 的二聚化与 HER3 通过 HER2/HER3 的重新激活同时发生，导致现在耐药的存活细胞中持续 HER2 磷酸化。研究发现，这些药物治疗诱导的过程是由配体释放介导的，包括调蛋白和β细胞蛋白，它们通过 HER2 激活 HER3 和 HER4。抗β细胞素抗体与易瑞莎联合使用可增强耐药细胞的抗增殖作用，而调蛋白和β细胞素等配体则使敏感的SKBR3细胞对易瑞莎产生耐药性。这些结果证明了药物诱导的自分泌事件可导致替代 HER 受体的激活，从而维持 HER2 磷酸化并介导乳腺癌细胞对 EGFR 酪氨酸激酶抑制剂 (TKI) 的耐药性，从而确定克服患者耐药性的治疗机会。
The response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses. Here we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both Förster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment–induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa. These results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients.
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