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

Publication date: Available online 28 June 2018
Source:Cell Metabolism
Author(s): 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
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.

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Teaser

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.


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