MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan–Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available “lung SqCC cell lines”, with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

MCL1 是一种抗凋亡 BCL2 家族成员，在各种恶性肿瘤中经常过度表达。然而，很少有报道描述 MCL1 在源自包括肺在内的气道的鳞状细胞癌 (SqCC) 中的作用。在这项研究中，我们检查了 MCL1 是否可以成为气道源性 SqCC 的新型药物靶点，对于这种情况，有效的分子靶向药物是不可用的。我们搜索了 Kaplan-Meier Plotter 数据库，发现高MCL1 mRNA 表达与下呼吸道（肺）或上呼吸道（头颈部）衍生的 SqCC 患者的较短生存期显着相关。我们还探索了 Expression Atlas 数据库并了解到真正的肺 SqCC 细胞系同时表达TP63和KRT5在公开可用的“肺 SqCC 细胞系”中，mRNA 极其稀少，HARA 细胞除外。HARA 细胞的生存高度依赖于 MCL1，在体外和体内暴露于多西紫杉醇 (DTX) 后，MCL1 耗尽的细胞无法生长，甚至数量下降。使用底特律 562 咽部 SqCC 细胞也获得了类似的体外实验结果，包括 3D 培养模型中的结果。这些发现表明，MCL1 沉默加 DTX 的联合治疗似乎对气道衍生的 SqCC 非常有效。