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

Fang Huang, Min Ni, Milind D. Chalishazar, Kenneth E. Huffman, Jiyeon Kim, Ling Cai, Xiaolei Shi, Feng Cai, Lauren G. Zacharias, Abbie S. Ireland, Kailong Li, Wen Gu, Akash K. Kaushik, Xin Liu, Adi F. Gazdar, Trudy G. Oliver, John D. Minna, Zeping Hu, Ralph J. DeBerardinis

Research output: Contribution to journalArticle

27 Scopus citations

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 (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. 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 ASCL1Low SCLC tumors and favorable combination with chemotherapy in in vivo models.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • IMPDH
  • lung cancer
  • metabolism
  • metabolomics
  • therapeutics

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Huang, F., Ni, M., Chalishazar, M. D., Huffman, K. E., Kim, J., Cai, L., Shi, X., Cai, F., Zacharias, L. G., Ireland, A. S., Li, K., Gu, W., Kaushik, A. K., Liu, X., Gazdar, A. F., Oliver, T. G., Minna, J. D., Hu, Z., & DeBerardinis, R. J. (Accepted/In press). Inosine Monophosphate Dehydrogenase Dependence in a Subset of Small Cell Lung Cancers. Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.06.005