Small cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here we investigated the contribution of the MAP kinase module MEK5/ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacological inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC.

中文翻译：

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MEK5-ERK5 激酶轴控制小细胞肺癌的脂质代谢。

小细胞肺癌 (SCLC) 是一种侵袭性肺癌，存活率低。虽然激酶通常在驱动肿瘤发生中起关键作用，但已知能促进 SCLC 发展的激酶却非常少。在这里，我们研究了 MAP 激酶模块 MEK5/ERK5 对 SCLC 生长的贡献。MEK5 和 ERK5 是 SCLC 细胞系在体外和体内的最佳存活和扩增所必需的。转录组学分析确定了 MEK5-ERK5 轴在 SCLC 细胞代谢（包括脂质代谢）中的作用。深入的脂质组学分析表明，MEK5/ERK5 的缺失扰乱了几种脂质代谢途径，包括控制胆固醇合成的甲羟戊酸途径。值得注意的是，MEK5/ERK5 的消耗使 SCLC 细胞对他汀类药物对甲羟戊酸途径的药理学抑制敏感。