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

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. Huang et al. identify ASCL1-high and -low metabolic subtypes in small cell lung cancer (SCLC), linked to de novo guanosine nucleotide synthesis. Using a clinically available inhibitor of the purine biosynthetic pathway, they demonstrate reduced growth of ASCL1^Low SCLC tumors and favorable combination with chemotherapy in in vivo models.