The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

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 MAPK 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 ofMEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5- ERK5-lipid metabolism axis that promotes the growth of SCLC. Significance: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.