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

Small cell lung cancer (SCLC), accounts for about 15 percent of all lung cancers, is a neuroendocrine type of carcinoma and is incredibly aggressive, with a dire diagnosis of 5% survival at 5 years. FDA-approved therapies for this disease are almost exclusively limited to chemotherapy and radiotherapy, to which resistance arises within months. Despite global sequencing efforts, few activating mutations have been discovered in SCLC tumors, and targetable alterations account for very small subsets of patients. Due to this lack of a strong oncogenic driver for conventional targeted therapy, SCLC has the potential to benefit from non-oncogene-addiction-based therapeutic approaches. We therefore focused on finding novel non-mutated pathways which could be targetable in SCLC. Restricting our search to kinases, a highly-targetable group of enzymes, we elucidated the active kinome of SCLC and upon identifying MEK5 as a SCLC-specific active kinase, further investigated the role of the MEK5-ERK5 kinase axis in this tumor type. We found that reduction in this axis in both human and murine SCLC cells causes increased susceptibility to apoptosis, and decreased subcutaneous tumor growth in vivo. Transcriptomic analysis of MEK5 and ERK5-knockdown cells showed downregulation of lipid metabolism pathways and SREBP target genes. Based on targeted lipidomics analyses of these same cells, which showed downregulated cholesterol ester species, we focused on the mevalonate arm of the SREBP pathway. RNAseq of murine small-cell lung cancer (SCLC) KP1 cells with MEK5 and ERK5 knockdowns, and control knockdowns (shGFP and shScr), as well as human SCLC cells NJH29 with MEK5 knockdown and control knockdowns (shGFP and shScr)