Palbociclib, a selective CDK4/6 inhibitor, enhances the effect of selumetinib in RAS-driven non-small cell lung cancer
Palbociclib, a selective CDK4/6 inhibitor, enhances the effect of selumetinib in RAS-driven non-small cell lung cancer
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Palbociclib 是一种选择性 CDK4/6 抑制剂，可增强 Selumetinib 在 RAS 驱动的非小细胞肺癌中的作用
DOI：
10.1016/j.canlet.2017.08.031
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发表时间：
2017-11-01
期刊：
影响因子：
9.7
通讯作者：
Zhou, Jianying
中科院分区：
文献类型：
--
作者：
Zhou, Jianya;Zhang, Shumeng;Zhou, Jianying
KRAS 是非小细胞肺癌 (NSCLC) 中最常见的突变癌基因之一。对 MEK 抑制剂单一疗法的耐药性是通过多种机制产生的。据报道 CDK4 与 KRAS 具有合成致死相互作用。在这项研究中，我们证明了 MEK 抑制剂 selumetinib 和 CDK4/6 抑制剂 palbociclib 在 RAS 驱动的 NSCLC 中的联合作用。在体外，具有 CDKN2A 突变的细胞系对司美替尼不敏感。我们使用 siRNA 和 CDK4 的药物抑制，发现 Selumetinib 和 palbociclib 组合可协同抑制 RAS 驱动的具有 CDKN2A 突变的 NSCLC 病例，但不能抑制野生型 CDKN2A 突变的 NSCLC 病例。联合治疗增强了生长抑制并增加了 G1 期细胞的数量。塞美替尼完全抑制 p-ERK，但不抑制 p-RB。添加 palbociclib 显着抑制 p-RB 并下调 survivin 表达。在体内，联合治疗抑制了 NSCLC 异种移植物的生长，这与 p-RB 水平降低、生存素下调和 Ki-67 染色减少相关。这些数据表明，palbociclib 和司美替尼联合治疗在 MS 驱动的 CDKN2A 突变 NSCLC 的临床前模型中有效。 (C) 2017 Elsevier B.V. 保留所有权利。
KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A. The combination treatment potentiated growth inhibition and increased the population of cells in G1 phase. Selumetinib completely inhibited p-ERK but not p-RB. The addition of palbociclib markedly inhibited p-RB and downregulated survivin expression. In vivo, the combination treatment inhibited the growth of NSCLC xenografts, which correlated with decreased levels of p-RB, downregulated survivin and decreased Ki-67 staining. These data suggest that the combination treatment of palbociclib and selumetinib is effective in preclinical models of MS-driven NSCLC with CDKN2A mutations. (C) 2017 Elsevier B.V. All rights reserved.