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 language | English (US) |
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Pages (from-to) | 369-382.e5 |
Journal | Cell Metabolism |
Volume | 28 |
Issue number | 3 |
DOIs | |
State | Published - Sep 4 2018 |
Keywords
- IMPDH
- lung cancer
- metabolism
- metabolomics
- therapeutics
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology