Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer
Transient PI3K Inhibition Induces Apoptosis and Overcomes HGF-Mediated Resistance to EGFR-TKIs in EGFR Mutant Lung Cancer
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DOI：
10.1158/1078-0432.ccr-10-1993
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Donev, Ivan S.;Wang, Wei;Yano, Seiji
目的：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），如吉非替尼和厄洛替尼，对EGFR突变型肺癌有良好的反应。然而，应答者几乎无一例外地获得耐药性。我们最近报道了肝细胞生长因子（HGF）通过激活MET诱导EGFR-TKI耐药，MET可恢复下游有丝分裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶（ERK）1/2和磷酸肌苷激酶(PI3K)/Akt信号。本研究的目的是确定抑制EGFR和MET的下游分子PI3K是否可以克服EGFR突变肺癌细胞PC-9和HCC827中hgf介导的EGFR- tki耐药。实验设计：研究I类PI3K抑制剂PI-103在体外和体内对hgf诱导的EGFR-TKI耐药的治疗作用。结果：与吉非替尼或埃洛替尼不同，即使在HGF存在的情况下，持续暴露于PI-103也能抑制PC-9和HCC827细胞的增殖。另一方面，在PC-9细胞与HGF高产成纤维细胞混合的吉非替尼耐药异种移植模型中，PI-103单药治疗并未抑制肿瘤生长。然而，PI-103联合吉非替尼成功地逆转了吉非替尼耐药肿瘤。考虑到PI-103半衰期短的体外实验表明，PI-103联合吉非替尼短暂暴露可持续抑制Akt磷酸化，但不抑制ERK1/2磷酸化，即使在HGF存在的情况下也可诱导肿瘤细胞凋亡。结论：这些结果表明，PI-103和吉非替尼短暂阻断PI3K/Akt通路可以通过诱导EGFR突变肺癌细胞凋亡来克服hgf介导的对EGFR- tkis的耐药性。临床癌症研究；17日(8);2260 - 9。(c) 2011年aacr。
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827.Experimental Design: We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo.Results: Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF.Conclusions: These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer. Clin Cancer Res; 17(8); 2260-9. (C) 2011 AACR.