Department of Pharmacology & Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Sci Rep. 2019 Dec 11;9(1):18842. doi: 10.1038/s41598-019-55376-4.
Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. The results support the hypothesis that combining MEK inhibitors with ALK inhibitor can overcome ALK inhibitor resistance, and identifies Bim, PARP and CDK1 as druggable targets for possible triple drug therapy.
间变性淋巴瘤激酶 (ALK) 重排是一小部分非小细胞肺癌的关键致癌驱动因素，使其对 ALK 酪氨酸激酶抑制剂 (TKI) 敏感。克唑替尼是一种第一代 ALK-TKI，与标准化疗相比具有更长的无进展生存期和更高的客观缓解率，具有优势。然而，临床获益受到耐药性的限制，通常在治疗一年内发生。在这项研究中，研究了克唑替尼和 MEK 抑制剂 selumetinib 在克唑替尼初治（H3122）和克唑替尼耐药（CR-H3122）ALK 阳性肺癌细胞中的联合作用。结果表明，联合治疗强烈抑制了 H3122 和 CR-H3122 细胞的生长，这是由于下游 RAS/MAPK 信号通路受到抑制，导致细胞凋亡增加和细胞增殖减少。与单独使用克唑替尼相比，药物联合使用还使凋亡介质 Bim 和细胞周期蛋白依赖性激酶抑制剂 p27 增加了 3 倍以上。研究结果支持了这样一种假设，即联合使用 MEK 抑制剂和 ALK 抑制剂可以克服 ALK 抑制剂耐药性，并确定 Bim、PARP 和 CDK1 是可能的三药治疗的可用药靶。
