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

Cell Metab. 2018 Sep 4;28(3):369-382.e5. doi: 10.1016/j.cmet.2018.06.005. Epub 2018 Jun 28.


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 (ASCL1High and ASCL1Low), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1Low cells and tumors from genetically engineered mice. ASCL1Low 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 ASCL1Low SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1Low cell growth in culture, selectively reduced growth of ASCL1Low xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1Low/MYCHigh SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.

Keywords: IMPDH; lung cancer; metabolism; metabolomics; therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cell Line, Tumor
  • Guanosine / metabolism*
  • Heterografts
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors
  • IMP Dehydrogenase / physiology*
  • Lung Neoplasms / enzymology*
  • Mice
  • Mice, Knockout
  • Small Cell Lung Carcinoma / enzymology*


  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Guanosine
  • IMP Dehydrogenase
  • IMPDH1, mouse
  • IMPDH2, mouse