Zhao Jane, Guerrero Adriana, Kelnar Kevin, Peltier Heidi J, Bader Andreas G
Mirna Therapeutics, Inc., 2150 Woodward Street, Suite 100, Austin 78744, TX, USA.
Mirna Therapeutics, Inc., 2150 Woodward Street, Suite 100, Austin 78744, TX, USA.
Lung Cancer. 2017 Jun;108:96-102. doi: 10.1016/j.lungcan.2017.02.020. Epub 2017 Mar 1.
EGFR 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.
Human 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.
Mimics 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.
Combined 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.
表皮生长因子受体酪氨酸激酶抑制剂（TKIs）被广泛用于治疗非小细胞肺癌（NSCLC），主要用于治疗具有激活突变的患者，而在野生型疾病中的反应较为有限。然而，即使是患有表皮生长因子受体（EGFR）突变的疾病，许多患者也无反应，大多数最初有反应的患者也不能完全缓解，几乎所有患者都会产生耐药性并不可避免地病情进展。能够改善这些结果的新治疗选择可能会带来巨大的临床益处。我们之前证明了厄洛替尼与肿瘤抑制性微小RNA miR-34a之间有强大的协同作用，使原发性耐药（EGFR野生型）的NSCLC细胞敏感，并恢复获得性耐药细胞的敏感性。在此，我们报告在类似实验中将miR-34a与新一代EGFR-TKIs联合使用的进一步研究结果。
评估对厄洛替尼有不同程度原发性和获得性耐药的人NSCLC细胞系对一系列miR-34a模拟物与阿法替尼、罗西替尼或奥希替尼联合剂量的敏感性。使用多种分析方法来表征对癌细胞增殖的影响是相加、拮抗还是协同作用。
在所有测试的EGFR突变细胞中，miR-34a模拟物与阿法替尼、罗西替尼或奥希替尼协同作用。在获得性耐药的细胞模型中观察到最佳且持续强烈的协同作用。在大多数EGFR野生型细胞中，miR-34a与罗西替尼和奥希替尼联合时协同作用也很明显，但与阿法替尼联合时则不明显。在广泛的剂量水平和药物比例下均观察到这种效应，在产生高水平抑制的剂量下具有最大协同作用，这种抑制水平超过了单一药物单独诱导的水平。
联合使用miR-34a和EGFR-TKIs可使EGFR野生型和突变型NSCLC细胞均产生协同敏感性，支持将这些联合用药作为克服NSCLC中对EGFR-TKIs原发性和获得性耐药的一种策略进行临床研究，这可能会改善治疗指数。
