PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors.
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, sensitizes lung cancer cells to treatment with epidermal growth factor receptor tyrosine kinase inhibitors.
复制标题
PD 0332991 是一种选择性细胞周期蛋白 D 激酶 4/6 抑制剂，可提高肺癌细胞对表皮生长因子受体酪氨酸激酶抑制剂治疗的敏感性
DOI：
10.18632/oncotarget.13069
复制
发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Liu M;Xu S;Wang Y;Li Y;Li Y;Zhang H;Liu H;Chen J
对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的获得性耐药是非小细胞肺癌（NSCLC）靶向治疗面临的主要挑战。我们研究了细胞周期蛋白D激酶4/6（CDK 4/6）抑制剂PD 0332991是否可以逆转人肺癌细胞的EGFR-TKI耐药性，并探讨了潜在的机制。我们发现，PD 0332991通过下调增殖和诱导凋亡以及G 0/G1细胞周期阻滞，增强了EGFR-TKI敏感（PC-9）和EGFR-TKI耐药（PC-9/AB 2）细胞中吉非替尼诱导的生长抑制。然后使用肿瘤异种移植物验证PD 0332991的体内作用。用PD 0332991和吉非替尼的组合治疗的小鼠具有最快的肿瘤消退和延迟的复发。来自接受组合治疗的小鼠的肿瘤表现出下调的增殖、上调的凋亡和较少的血管生成。最后，对EGFR-TKI获得性耐药的肺腺癌患者接受PD 0332991探索性治疗。1例吉非替尼耐药患者在PD 0332991治疗后出现临床缓解。这些发现表明PD 0332991逆转NSCLC细胞中获得性EGFR-TKI耐药，并可能为具有EGFR-TKI耐药的NSLSC患者提供新的治疗策略。
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge to targeted therapy for non-small cell lung cancer (NSCLC). We investigated whether a cyclin D kinase 4/6 (CDK4/6) inhibitor, PD 0332991, could reverse EGFR-TKI resistance in human lung cancer cells and explored the underlying mechanisms. We found that PD 0332991 potentiated gefitinib-induced growth inhibition in both EGFR-TKI-sensitive (PC-9) and EGFR-TKI-resistant (PC-9/AB2) cells by down-regulating proliferation and inducing apoptosis and G0/G1 cell cycle arrest. Tumor xenografts were then used to verify the effects of PD 0332991 in vivo. Mice treated with a combination of PD 0332991 and gefitinib had the fastest tumor regression and delayed relapse. Tumors from mice receiving the combination treatment exhibited down-regulated proliferation, up-regulated apoptosis, and less angiogenesis. Finally, lung adenocarcinoma patients with acquired resistance to EGFR-TKIs were given an exploratory treatment of PD 0332991. One patient with gefitinib resistance exhibited clinical remission after treatment with PD 0332991. These findings suggest PD 0332991 reverses acquired EGFR-TKI-resistance in NSCLC cells, and may provide a novel treatment strategy for NSLSC patients with EGFR-TKI resistance.