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

Summary 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 polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1 Low cell growth in culture, selectively reduced growth of ASCL1 Low xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1 Low /MYC High SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.