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首页> 外文期刊>Cancer biology & therapy >A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS
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A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS

机译：CDK4 / 6抑制剂增强紫杉醇在具有突变KRAS和野生型KRAS的肺腺癌细胞中的细胞毒性

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The KRAS gain-of-function mutation confers intrinsic resistance to targeted anticancer drugs and cytotoxic chemotherapeutic agents, ultimately leading to treatment failure. KRAS mutation frequency in lung adenocarcinoma is ~15-30%. Novel therapeutic strategies should be developed to improve clinical outcomes in these cases. Deregulation of the p16/cyclin-dependent kinase (CDK) 4/retinoblastoma (Rb) pathway is frequently observed in various cancers and it represents an attractive therapeutic target. We compared the antitumor efficacy of genetically knocked-down CDK4 and a pharmacological inhibitor of CDK4/6, CINK4, in KRAS mutation-positive lung adenocarcinoma cells. We also investigated changes in anti-proliferative activity and downstream molecules with these treatments in combination with paclitaxel. CDK4 short interfering RNA (siRNA) significantly increased paclitaxel sensitivity in KRAS mutation-positive H23 cells. CINK4 demonstrated concentration- and time-dependent anti-proliferative activity in 5 adenocarcinoma lines. CINK4 induced G1 arrest by downregulating the p16/cyclin D1/Rb pathway, resulting in apoptotic induction via increased expression of cleaved caspase3, cleaved PA RP and Bax. Combined CINK4 and paclitaxel produced synergistic anti-proliferative activity and increased apoptosis through reduced cyclin D1 and Bcl-2 in KRAS mutation-positive cancer cells. These data suggest CDK4 is a promising target for development of anticancer drugs and CINK4 combined with paclitaxel may be an effective therapeutic strategy for enhancing anti-tumor efficacy in KRAS mutation-positive lung adenocarcinoma.
机译：KRAS功能获得突变赋予对靶向抗癌药和细胞毒性化疗药物的内在抗性，最终导致治疗失败。肺腺癌的KRAS突变频率约为15-30％。在这些情况下，应开发新的治疗策略以改善临床疗效。在各种癌症中经常观察到p16 /细胞周期蛋白依赖性激酶（CDK）4 /成视网膜细胞瘤（Rb）通路的失控，它代表了有吸引力的治疗靶标。我们比较了基因敲除的CDK4和CDK4 / 6的药理抑制剂CINK4在KRAS突变阳性的肺腺癌细胞中的抗肿瘤作用。我们还研究了与紫杉醇联合使用这些治疗方法的抗增殖活性和下游分子的变化。 CDK4短干扰RNA（siRNA）在KRAS突变阳性H23细胞中显着增加了紫杉醇敏感性。 CINK4在5种腺癌细胞系中表现出浓度和时间依赖性的抗增殖活性。 CINK4通过下调p16 / cyclin D1 / Rb途径诱导G1阻滞，通过裂解的caspase3，裂解的PA RP和Bax的表达增加导致凋亡诱导。 CINK4和紫杉醇联合使用可通过减少KRAS突变阳性癌细胞中的细胞周期蛋白D1和Bcl-2产生协同的抗增殖活性并增加细胞凋亡。这些数据表明CDK4是抗癌药物开发的有希望的目标，CINK4与紫杉醇联合可能是增强KRAS突变阳性肺腺癌抗肿瘤功效的有效治疗策略。

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