Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors
Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors
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DOI：
10.1073/pnas.1018001108
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Arteaga, Carlos L.
中科院分区：
文献类型：
--
作者：
Chakrabarty, Anindita;Sanchez, Violeta;Arteaga, Carlos L.
我们检测了PI3K抑制剂XL147对具有PI3K结构性激活的人乳腺癌细胞株的影响。XL147剂量依赖性抑制细胞生长，抑制PI3K/AKT/TOR信号转导通路PARKT和pS6的表达。在HER2过表达的细胞中，抑制PI3K之后是上调包括HER3在内的多个受体酪氨酸激酶的表达和磷酸化。FoxO1和FOXO3a转录因子的敲除抑制了PI3K对HER3、InsR、IGF1R和FGFR2 mRNAs的诱导。在HER2(+)细胞中，用siRNA敲除HER3或与HER2抑制剂曲妥珠单抗或拉帕替尼共同处理可增强XL147诱导的细胞死亡和对PACK和pS6的抑制。曲妥珠单抗和拉帕替尼分别与XL147协同抑制PACT和已建立的BT474异种移植瘤的生长。这些数据表明，PI3K拮抗剂将抑制AKT，并缓解受体酪氨酸激酶表达及其活性的抑制。这种反馈的解除限制了对PI3K/AKT通路的持续抑制，并减弱了对这些药物的反应。因此，如果作为单一药物使用，PI3K途径抑制剂的总体临床活性可能有限。在HER2过表达的乳腺癌患者中，PI3K抑制剂应与HER2/HER3拮抗剂联合使用。
We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2(+) cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.