In-depth analysis shows synergy between erlotinib and miR-34a.
In-depth analysis shows synergy between erlotinib and miR-34a.
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DOI：
10.1371/journal.pone.0089105
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Bader AG
中科院分区：
文献类型：
--
作者：
Zhao J;Kelnar K;Bader AG
针对表皮生长因子受体（EGFR-TKI）的酪氨酸激酶抑制剂，如厄洛替尼，在非小细胞肺癌（NSCLC）的有限部分中有效。然而，大多数NSCLC和其他癌症类型仍然具有耐药性。模仿内源性肿瘤抑制miRNA的治疗性miRNA模拟物通过同时抑制多个癌基因来抑制肿瘤生长，因此可用于增加药物敏感性。在这里，我们研究了miR-34 a和厄洛替尼的关系，并确定了在原发性和获得性厄洛替尼耐药的NSCLC细胞中组合的治疗活性。还在一组肝细胞癌细胞（HCC）中测试了药物组合，这是一种已知对厄洛替尼难治的癌症类型。使用多种分析方法，确定药物诱导的癌细胞增殖抑制，以揭示累加、拮抗或协同效应。我们的数据显示，在所有测试的癌细胞中，埃罗替尼和miR-34 a模拟物之间存在强的协同相互作用。在不同剂量水平和药物比例范围内观察到协同作用，分别将厄洛替尼和miR-34 a的IC 50剂量需求降低高达46倍和13倍。在提供高水平的癌细胞抑制的剂量下检测到最大协同作用，所述高水平的癌细胞抑制超过由单独的单一药剂诱导的水平，因此具有临床相关性。数据表明，大多数非小细胞肺癌和以前不适合厄洛替尼的其他癌症在与基于miR-34 a的疗法联合使用时可能对该药物敏感。
Tyrosine kinase inhibitors directed against epidermal growth factor receptor (EGFR-TKI), such as erlotinib, are effective in a limited fraction of non-small cell lung cancer (NSCLC). However, the majority of NSCLC and other cancer types remain resistant. Therapeutic miRNA mimics modeled after endogenous tumor suppressor miRNAs inhibit tumor growth by repressing multiple oncogenes at once and, therefore, may be used to augment drug sensitivity. Here, we investigated the relationship of miR-34a and erlotinib and determined the therapeutic activity of the combination in NSCLC cells with primary and acquired erlotinib resistance. The drug combination was also tested in a panel of hepatocellular carcinoma cells (HCC), a cancer type known to be refractory to erlotinib. Using multiple analytical approaches, drug-induced inhibition of cancer cell proliferation was determined to reveal additive, antagonistic or synergistic effects. Our data show a strong synergistic interaction between erlotinib and miR-34a mimics in all cancer cells tested. Synergy was observed across a range of different dose levels and drug ratios, reducing IC50 dose requirements for erlotinib and miR-34a by up to 46-fold and 13-fold, respectively. Maximal synergy was detected at dosages that provide a high level of cancer cell inhibition beyond the one that is induced by the single agents alone and, thus, is of clinical relevance. The data suggest that a majority of NSCLC and other cancers previously not suited for erlotinib may prove sensitive to the drug when used in combination with a miR-34a-based therapy.
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影响因子：
11.2
作者：
Bader AG;Brown D;Winkler M
通讯作者：
Winkler M
捕获microRNA结合的mRNA将肿瘤抑制器miR-34a识别为生长因子信号传导的调节剂。
影响因子：
4.5
作者：
Lal A;Thomas MP;Altschuler G;Navarro F;O'Day E;Li XL;Concepcion C;Han YC;Thiery J;Rajani DK;Deutsch A;Hofmann O;Ventura A;Hide W;Lieberman J
通讯作者：
Lieberman J
影响因子：
5.3
作者：
Kawano, Osamu;Sasaki, Hidefumi;Fujii, Yoshitaka
通讯作者：
Fujii, Yoshitaka
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.
DOI：
10.1038/nrd4140
发表时间：
2013-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Ling H;Fabbri M;Calin GA
通讯作者：
Calin GA