Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
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DOI：
10.18632/oncotarget.9153
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Kopetz S
中科院分区：
文献类型：
--
作者：
Lee MS;Helms TL;Feng N;Gay J;Chang QE;Tian F;Wu JY;Toniatti C;Heffernan TP;Powis G;Kwong LN;Kopetz S
虽然MEK抑制剂的疗效正在KRAS突变型结直肠癌（CRC）中进行研究，但MEK抑制剂单药治疗的早期临床试验并未显示出显著的抗肿瘤活性。对MEK抑制剂单药治疗的耐药性是通过多种聚集在ERK再活化中的机制产生的。由于ERK增加细胞周期蛋白D的表达，并增加进入细胞周期，我们假设MEK抑制剂和CDK 4/6抑制剂的组合将具有协同抗肿瘤活性，并导致体内肿瘤消退。MEK和CDK 4/6抑制剂的组合在体外协同抑制癌细胞生长，并在细胞系和患者来源的异种移植物模型中引起体内肿瘤消退。联合治疗显着降低磷酸化核糖体蛋白S6在体外和体内的水平，并减少Ki 67染色在体内。我们对一组用MEK抑制剂MEK 162、CDK 4/6抑制剂palbociclib或其组合处理的11种KRAS突变CRC细胞系进行了体外增殖、集落形成、凋亡和衰老测定以及蛋白质印迹。我们还用MEK抑制剂曲美替尼、CDK 4/6抑制剂palbociclib或其组合治疗了4种KRAS突变型CRC细胞系和患者来源的异种移植物，并进行了免疫组织化学和反相蛋白阵列分析。MEK和CDK 4/6的联合抑制在KRAS突变型CRC的临床前模型中是有效的，并且证明了计划在难治性KRAS突变型CRC患者中进行的II期临床试验是合理的。MEK和CDK 4/6抑制剂的组合在KRAS突变结肠直肠癌模型中的体外和体内功效。
Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo. The combination of MEK and CDK4/6 inhibitors synergistically inhibited cancer cell growth in vitro and caused tumor regression in vivo in cell line and patient-derived xenograft models. Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo. We performed in vitro proliferation, colony formation, apoptosis, and senescence assays, and Western blots, on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162, the CDK4/6 inhibitor palbociclib, or the combination. We also treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib, the CDK4/6 inhibitor palbociclib, or the combination, and performed immunohistochemical and reverse phase protein array analysis. Combined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
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影响因子：
11.2
作者：
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通讯作者：
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