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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Huang, F; Ni, M; Chalishazar, MD; Huffman, KE; Kim, J; Cai, L; Shi, X; Cai, F; Zacharias, LG; Ireland, AS; Li, K; Gu, W; Kaushik, AK; Liu, X; Gazdar, AF; Oliver, TG; Minna, JD; Hu, Z; DeBerardinis, RJ

Published Date

  • September 4, 2018

Published In

Volume / Issue

  • 28 / 3

Start / End Page

  • 369 - 382.e5

PubMed ID

  • 30043754

Pubmed Central ID

  • PMC6125205

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2018.06.005

Language

  • eng

Conference Location

  • United States