Effect of PF-02341066 and radiation on non-small cell lung cancer cells.
Effect of PF-02341066 and radiation on non-small cell lung cancer cells.
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DOI：
10.3892/or.2012.2198
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发表时间：
2013-03
期刊：
影响因子：
4.2
通讯作者：
Saha D
中科院分区：
文献类型：
--
作者：
Tumati V;Kumar S;Yu L;Chen B;Choy H;Saha D
最近，棘皮动物微管相关蛋白样4（EML 4）和间变性淋巴瘤激酶（ALK）的融合蛋白在非小细胞肺癌（NSCLC）患者中被发现。此外，在许多侵袭性NSCLC病例中发现磷酸化c-Met的内源性表达增加。PF-02341066（克唑替尼）是一种新型c-Met和EML 4-ALK双重抑制剂，临床前研究表明，ALK抑制剂治疗可导致异种移植模型中的肿瘤急剧消退。PF-02341066的I期试验产生了53%的缓解率和79%的疾病控制率。我们在多种已建立的c-Met和EML 4-ALK表达水平不同的NSCLC细胞系中评估了克唑替尼作为潜在放射增敏剂的作用。通过5种NSCLC细胞系（A549、H460、H3122、H2228和H1993）和体内异种移植研究中的存活细胞分数、细胞周期分布、细胞凋亡、DNA双链断裂修复，确定了电离辐射（IR）和PF-02341066的联合作用。单独使用PF-02341066或PF-02341066 + IR处理NSCLC细胞未显著改变细胞放射敏感性、DNA修复动力学和细胞周期分布;在PF-02341066 + IR联合治疗中，未观察到肿瘤生长延迟的显著增强。Met抑制导致聚集在Akt信号传导上的平行途径激活，从而消除任何辐射增敏作用。尽管PF-02341066是一种能够抑制EML 4-ALK或c-Met阳性肿瘤生长的有效疗法，但它不影响肿瘤细胞系的固有辐射反应。在本研究中，我们证明PF-02341066不会增强一组NSCLC细胞系的辐射敏感性。
Recently, a fusion protein of echinoderm microtubule associated protein like-4 (EML4) and anaplastic lymphoma kinase (ALK) has been found in non-small cell lung cancer (NSCLC) patients. In addition, endogenous expression of phosphorylated c-Met was found to be increased in many invasive NSCLC cases. PF-02341066 (crizotinib) is a novel dual c-Met and EML4-ALK inhibitor, and preclinical studies have shown that treatment with ALK inhibitors leads to drastic tumor regression in xenograft models. A phase I trial of PF-02341066 yielded a 53% response rate and a disease control rate of 79%. We evaluated crizotinib as a potential radiation-sensitizing agent in multiple established NSCLC cell lines with varying expression levels of c-Met and EML4-ALK. The combined effect of ionizing radiation (IR) and PF-02341066 was determined by the surviving cell fraction, cell cycle distribution, apoptosis, DNA double-strand break repair in 5 NSCLC cell lines (A549, H460, H3122, H2228 and H1993) and in in vivo xenograft studies. Treatment of NSCLC cells with either PF-02341066 alone or PF-02341066 + IR did not significantly alter cellular radiosensitivity, DNA repair kinetics and cell cycle distribution; no significant enhancement of tumor growth delay was noted in response to the combined treatment of PF-02341066 + IR. EML4-ALK and c-Met inhibition leads to activation of parallel pathways that converge on Akt signaling which abrogates any radiation-sensitizing effect. Although PF-02341066 is an effective therapy able to suppress tumor growth in tumors that exhibit positivity for either EML4-ALK or c-Met, it did not affect the intrinsic radiation response of tumor cell lines. In the present study, we demonstrated that PF-02341066 did not enhance radiation sensitivity in a panel of NSCLC cell lines.