Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205.
Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Int J Biol Sci. 2018 Jul 13;14(10):1221-1231. doi: 10.7150/ijbs.25488. eCollection 2018.
Small cell lung cancer (SCLC) is highly lethal with no effective therapy. Wee1 kinase inhibitor AZD1775 (MK-1775) and mTOR kinase inhibitor MLN0128 (TAK228) are in clinical trials for relapsed SCLC and recurrent lung cancer, respectively. However, there is no preclinical data combining these two drugs in human cancers. In this study, we set to investigate the combinatorial anti-tumor effects of AZD1775 and MLN0128 on two human SCLC cell lines H69 and H82 in vitro and in vivo. We have found that AZD1775 or MLN0128 treatment results in remarkably suppressed cell proliferation and increased cell death in vitro, what's more, the salient finding here is the potent anti-tumor effect observed in combinatorial treatment in H82 xenograft tumor. Importantly, we have first observed marked induction of ER stress and CHOP-dependent SCLC cell apoptosis in MLN0128 and AZD1775-primed cells. Our study has first provided preclinical evidence that combination of AZD1775 and MLN0128 could be a novel effective therapy for advanced SCLC patients.
小细胞肺癌（SCLC）是一种高度致命的疾病，目前尚无有效的治疗方法。Wee1 激酶抑制剂 AZD1775（MK-1775）和 mTOR 激酶抑制剂 MLN0128（TAK228）分别正在进行用于治疗复发性 SCLC 和复发性肺癌的临床试验。然而，目前在人类癌症中尚无联合使用这两种药物的临床前数据。在这项研究中，我们旨在研究 AZD1775 和 MLN0128 对两种人 SCLC 细胞系 H69 和 H82 的体外和体内联合抗肿瘤作用。我们发现，AZD1775 或 MLN0128 处理可显著抑制体外细胞增殖并增加细胞死亡，更重要的是，这里的突出发现是在 H82 异种移植肿瘤的联合治疗中观察到的强大抗肿瘤作用。重要的是，我们首次观察到在 MLN0128 和 AZD1775 引发的细胞中明显诱导内质网应激和 CHOP 依赖性 SCLC 细胞凋亡。我们的研究首次提供了临床前证据，表明联合使用 AZD1775 和 MLN0128 可能是治疗晚期 SCLC 患者的一种新的有效疗法。
