Synergy between next generation EGFR tyrosine kinase inhibitors and miR-34a in the inhibition of non-small cell lung cancer.
Synergy between next generation EGFR tyrosine kinase inhibitors and miR-34a in the inhibition of non-small cell lung cancer.
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DOI：
10.1016/j.lungcan.2017.02.020
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发表时间：
2017-06
期刊：
影响因子：
5.3
通讯作者：
Jane Zhao;A. Guerrero;K. Kelnar;Heidi J. Peltier;A. Bader
中科院分区：
文献类型：
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作者：
Jane Zhao;A. Guerrero;K. Kelnar;Heidi J. Peltier;A. Bader
目的 EGFR 酪氨酸激酶抑制剂 (TKI) 广泛用于治疗 NSCLC，主要是具有激活突变的患者，对野生型疾病的反应更为有限。然而，即使患有 EGFR 突变疾病，许多患者也无法做出反应，大多数最初有反应的患者未能完全反应，并且几乎所有人都会产生耐药性并不可避免地进展。改善这些结果的新治疗选择可以带来巨大的临床益处。我们之前证明了厄洛替尼和肿瘤抑制因子 microRNA miR-34a 之间的强大协同作用，使具有原发性耐药（EGFR 野生型）的 NSCLC 细胞变得敏感，并恢复具有获得性耐药的细胞的敏感性。在这里，我们报告了在类似实验中将 miR-34a 与新一代 EGFR-TKI 相结合的进一步研究结果。材料和方法对厄洛替尼具有不同程度的原发性和获得性耐药性的人类 NSCLC 细胞系进行了评估，以评估其对 miR-34a 模拟物和阿法替尼、罗西替尼或奥希替尼的广泛组合剂量的敏感性。使用多种分析方法来表征对癌细胞增殖的影响，如加成、拮抗或协同。结果在所有测试的 EFGR 突变细胞中，miR-34a 的模拟物与阿法替尼、罗西替尼或奥西替尼具有协同作用。在具有获得性耐药性的细胞模型中观察到了最佳且一致的强协同作用。在大多数 EGFR 野生型细胞中，miR-34a 与罗西替尼和奥西替尼联合使用时，协同作用也很明显，但与阿法替尼联合使用时则不然。在广泛的剂量水平和药物比率范围内观察到效果，在剂量上产生最大协同作用，产生高水平的抑制，超出了单独使用单一药物可能诱导的抑制水平。 结论 miR-34a 和 EGFR-TKI 组合可协同增敏 EGFR 野生型和突变型 NSCLC 细胞，支持将这些组合作为克服原发性和获得性耐药的策略进行临床研究 EGFR-TKIs 治疗 NSCLC，可能具有改善的治疗指数。
ObjectivesEGFR tyrosine kinase inhibitors (TKIs) are widely used to treat NSCLC, primarily patients with activating mutations, with more limited response in wild-type disease. However, even with EGFR-mutated disease, many patients fail to respond, most who initially respond fail to respond completely, and almost all develop resistance and inevitably progress. New therapeutic options that improve these outcomes could provide substantial clinical benefit. We previously demonstrated strong synergistic effects between erlotinib and the tumor suppressor microRNA miR-34a, sensitizing NSCLC cells with primary resistance (EGFR wild-type) and restoring sensitivity in cells with acquired resistance. Here, we report results of further research combining miR-34a with newer generation EGFR-TKIs in similar experiments.Materials and methodsHuman NSCLC cell lines with varying degrees of primary and acquired resistance to erlotinib were assessed for sensitivity to a broad set of combined doses of miR-34a mimic and afatinib, rociletinib or osimertinib. Multiple analytical approaches were used to characterize effects on cancer cell proliferation as additive, antagonistic or synergistic.ResultsMimics of miR-34a synergized with afatinib, rociletinib or osimertinib in all EFGR-mutant cells tested. Best and consistently strong synergy was observed in cell models with acquired resistance. Synergy was also evident in most EGFR wild-type cells with miR-34a combined with rociletinib and osimertinib, but not with afatinib. The effects were observed across a broad range of dose levels and drug ratios, with maximal synergy at doses yielding high levels of inhibition beyond those possible to be induced by the single agents alone.ConclusionCombined miR-34a and EGFR-TKIs synergistically sensitize both EGFR wild-type and mutant NSCLC cells, supporting clinical investigation of these combinations as a strategy to overcome both primary and acquired resistance to EGFR-TKIs in NSCLC, possibly with an improved therapeutic index.