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

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

Author information

1
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
4
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: zeping_hu@mail.tsinghua.edu.cn.
7
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ralph.deberardinis@utsouthwestern.edu.

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.

KEYWORDS:

IMPDH; lung cancer; metabolism; metabolomics; therapeutics

PMID:
30043754
PMCID:
PMC6125205
[Available on 2019-09-04]
DOI:
10.1016/j.cmet.2018.06.005

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