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.

由于缺乏靶标，在小细胞肺癌（SCLC）的治疗方面几乎没有进展。MCL1是抗凋亡BCL-2家族的成员，可能成为包括SCLC在内的几种癌症的治疗靶标。但是，抗凋亡BCL-2家族的表达谱是否影响MCL1抑制策略尚不清楚。从2001年至2017年间连续被诊断为SCLC且先前曾在京都大学医院（日本京都）进行过手术的患者中创建了组织芯片（TMA）。我们使用了MCL1抑制剂S63845来评估SCLC中的细胞毒性能力细胞系，包括体外和体内患者来源的细胞系。S63845与navitoclax（双BCL-X _{L）的组合}/ BCL-2抑制剂，也用于检查抗凋亡BCL-2家族的全面抑制。从患者的手术切除SCLC一个TMA的免疫组织化学证实低BCL-X高MCL1表达_大号和BCL-2是最常见的表达谱。S63845是有效的在高MCL1-和低BCL-X_大号-表达SCLC细胞系。S63845在体外诱导BAK依赖性细胞凋亡，并在体内模型中证实了抗肿瘤功效。虽然击倒的BCL X _LBCL-2和BCL-2改善了S63845的细胞毒性活性，并与navitoclax联合使用增加了抗肿瘤细胞毒性，在体内研究中，S63845与navitoclax的治疗范围狭窄。我们的研究表明MCL1抑制疗法可以应用于高MCL1-和低BCL-X_大号-表达SCLC患者。