Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers.

ABSTRACT: Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1^High and ASCL1^Low), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1^Low cells and tumors from genetically engineered mice. ASCL1^Low tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1^Low SCLC. IMPDH inhibition reduced RNA

SUBMITTER: Huang F 

PROVIDER: S-EPMC6125205 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature