MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression
MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression
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DOI：
10.1038/s41419-020-2379-2
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发表时间：
2020-03-09
影响因子：
9
通讯作者：
Hirai, Toyohiro
中科院分区：
文献类型：
--
作者：
Yasuda, Yuto;Ozasa, Hiroaki;Hirai, Toyohiro
由于缺乏靶点，小细胞肺癌(SCLC)的治疗进展甚微。MCL1是抗凋亡bcl2家族的成员之一，可能是包括小细胞肺癌在内的几种癌症的治疗靶点。然而，抗凋亡的bcl2家族的表达谱是否会影响MCL1的抑制策略尚不清楚。组织微阵列(TMA)是从2001年至2017年期间在京都大学医院(京都)接受过手术的连续患者中创建的。我们使用MCL1抑制剂S63845在体外和体内评估了SCLC细胞系的细胞毒能力，包括患者来源的细胞系。将S63845与bclx-X-L/bcl2双抑制剂维妥克拉克斯联合应用，观察其对抗凋亡bcl2家族的综合抑制作用。手术切除的小细胞肺癌患者的TMA免疫组织化学染色显示，mcl1高表达，bclX低表达，L和bcl2是最常见的表达谱。S63845对mcl1高表达和bclX L低表达的小细胞肺癌细胞株均有效。S63845在体外诱导BAK依赖的细胞凋亡，体内实验证实其抗肿瘤作用。尽管bclX-L和bcl2基因敲除可提高S63845的细胞毒活性，且其与奈替克拉克斯联合应用可提高其抗肿瘤细胞毒作用，但体内实验显示其联合应用的治疗范围较窄。我们的研究建议对mcl1高表达和bclX-L低表达的小细胞肺癌患者进行mcl1抑制治疗。
There have been few advances in the treatment of small-cell lung cancer (SCLC) because of the lack of targets. MCL1, a member of the anti-apoptotic BCL-2 family, may be a treatment target in several cancers, including SCLC. However, whether the expression profile of the anti-apoptotic BCL-2 family affects MCL1 inhibition strategy is unknown. A tissue microarray (TMA) was created from consecutive patients who were diagnosed with SCLC and had previously undergone surgery at Kyoto University Hospital (Kyoto, Japan) between 2001 and 2017. We used S63845, a MCL1 inhibitor, to assess the cytotoxic capacity in SCLC cell lines including a patient-derived cell line in vitro and in vivo. The combination of S63845 with navitoclax, a double BCL-X-L/BCL-2 inhibitor, was also employed to examine the comprehensive inhibition of the anti-apoptotic BCL-2 family. Immunohistochemistry of a TMA from patients with surgically resected SCLC demonstrated high MCL1 expression with low BCL-X-L and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1- and low BCL-X-L-expressing SCLC cell lines. S63845 induced BAK-dependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BCL-X-L and BCL-2 improved the cytotoxic activity of S63845 and its combination with navitoclax increased the anti-tumor cytotoxicity, the therapeutic range of S63845 with navitoclax was narrow in in vivo studies. Our study suggests MCL1 inhibition therapy be applied for high MCL1- and low BCL-X-L-expressing SCLC patients.