Enhanced gefitinib-induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia-mutated kinase inhibition in non-small-cell lung cancer cells.
Enhanced gefitinib-induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia-mutated kinase inhibition in non-small-cell lung cancer cells.
复制标题
在非小细胞肺癌细胞中通过共济失调毛细血管扩张突变激酶抑制增强吉非替尼诱导的表皮生长因子受体途径的抑制。
DOI：
10.1111/cas.12899
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发表时间：
2016-04
期刊：
影响因子：
5.7
通讯作者：
Tashiro S
中科院分区：
文献类型：
--
作者：
Misumi K;Sun J;Kinomura A;Miyata Y;Okada M;Tashiro S
表皮生长因子受体（EGFR）酪氨酸激酶信号通路调节细胞活动。EGFR酪氨酸激酶抑制剂（EGFR-TKI）抑制由体细胞EGFR基因突变组成型激活的EGFR通路，并显著改善了非小细胞肺癌（NSCLC）患者的预后。然而，包括阻力在内的一些问题仍有待解决。最近，EGFR ‐ TKI和细胞毒性药物的联合治疗已被证明可改善NSCLC患者的预后。为了增强EGFR-TKI的抗癌作用，我们检查了EGFR通路与共济失调毛细血管扩张突变（ATM）信号通路的交叉作用。ATM是DNA损伤反应中的关键蛋白激酶，已知其磷酸化EGFR下游因子Akt。我们发现，ATM抑制剂KU55933和EGFR-TKI吉非替尼的组合导致携带敏感EGFR突变的NSCLC细胞系中的协同细胞生长抑制和细胞凋亡诱导。我们还发现KU55933增强了EGFR和/或其下游因子磷酸化的吉非替尼依赖性抑制。ATM抑制可能有助于吉非替尼依赖性抑制EGFR和/或其下游因子的磷酸化，从而对具有敏感EGFR突变的NSCLC细胞发挥抗癌作用。
The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. The EGFR tyrosine kinase inhibitors (EGFR‐TKIs) repress the EGFR pathway constitutively activated by somatic EGFR gene mutations and have drastically improved the prognosis of non‐small‐cell lung cancer (NSCLC) patients. However, some problems, including resistance, remain to be solved. Recently, combination therapy with EGFR‐TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anticancer effects of EGFR‐TKIs, we examined the cross‐talk of the EGFR pathways with ataxia telangiectasia‐mutated (ATM) signaling pathways. ATM is a key protein kinase in the DNA damage response and is known to phosphorylate Akt, an EGFR downstream factor. We found that the combination of an ATM inhibitor, KU55933, and an EGFR‐TKI, gefitinib, resulted in synergistic cell growth inhibition and induction of apoptosis in NSCLC cell lines carrying the sensitive EGFR mutation. We also found that KU55933 enhanced the gefitinib‐dependent repression of the phosphorylation of EGFR and/or its downstream factors. ATM inhibition may facilitate the gefitinib‐dependent repression of the phosphorylation of EGFR and/or its downstream factors, to exert anticancer effects against NSCLC cells with the sensitive EGFR mutation.