目的:随机试验表明,酪氨酸激酶抑制剂(TKI)和化疗联合治疗表皮生长因子受体突变的非小细胞肺癌(NSCLC)是有益的。对于间变性淋巴瘤激酶重排(ALK+)NSCLC,该组合的前瞻性试验结果尚不可用,甚至尚未在体外进行彻底研究.在这项研究中,我们使用ALK+NSCLC的体外模型研究了TKI和化疗的组合。
方法:ALK+细胞系模型H3122、H2228和DFCI032对ALK受体TKIs具有不同的主要抗性。我们研究了短期(活力测定)和长期(集落形成测定)细胞毒性,凋亡,和响应于试剂组合的细胞信号传导。我们选择了最常用的药物,阿列替尼,顺铂,和培美曲塞,来研究组合效应。
结果:在短期暴露的组合实验中,观察到TKI和培美曲塞之间的协同作用,而顺铂有拮抗作用。在长期的实验中,顺铂和TKI的组合在所有细胞系中均具有协同作用,而没有观察到与培美曲塞的协同作用。在化疗和TKI序列中,在三个模型中的两个模型中,顺铂和TKI的细胞毒性更高。在TKI敏感的H3122细胞系中,化疗和TKI联合治疗可增加细胞凋亡。有趣的是,培美曲塞治疗导致ALK激活,被TKI废除了。
结论:在ALK+模型中联合TKI和化疗具有一些克服原发性TKI耐药的协同作用。然而,协同作用根据化疗剂的不同而不同,细胞毒性试验,和使用的细胞系。有必要进行前瞻性临床试验,以充分描述ALK+NSCLC中TKI联合化疗的潜力。
OBJECTIVE: Randomized trials have shown the benefit of combining tyrosine kinase inhibitors (TKI) and chemotherapy in the treatment of epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). For anaplastic lymphoma kinase-rearranged (ALK+) NSCLC, prospective trial results of the
combination are not available and have not even been thoroughly investigated in vitro. In this study, we investigated combinations of TKI and chemotherapy using in vitro models of ALK+ NSCLC.
METHODS: ALK+ cell line models H3122, H2228, and DFCI032 with differing primary resistance to ALK receptor TKIs were used. We investigated short-(viability assay) and long-term (colony-formation assay) cytotoxicity, apoptosis, and cell signaling in response to the combinations of agents. We selected the most commonly used agents, alectinib, cisplatin, and pemetrexed, to investigate the combination effects.
RESULTS: In the
combination experiments with short-term exposure, synergism between TKI and pemetrexed was observed, while cisplatin had antagonistic effects. In the long-term experiments, the
combination of cisplatin and TKI was synergistic in all lines, while no synergism was observed with pemetrexed. Among the chemotherapy and TKI sequences, cisplatin followed by TKI was more cytotoxic than the opposite in two out of the three models. In the TKI-sensitive H3122 cell line, the
combination of chemotherapy and TKI
combination increased apoptosis. Interestingly, pemetrexed treatment resulted in the activation of ALK, which was abolished with TKI.
CONCLUSIONS: Combining TKI and chemotherapy in ALK+ models has some synergistic effects that overcome primary TKI resistance. However, the synergy varies depending on the chemotherapeutic agent, cytotoxic assay, and the cell line used. Prospective clinical trials are warranted to fully characterize the potential of
combination chemotherapy with TKIs in ALK+ NSCLC.