期刊
CELL METABOLISM
卷 28, 期 3, 页码 369-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.06.005
关键词
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资金
- NIH [1R35CA22044901, R01CA187457]
- V Foundation (Translational Award)
- Robert A. Welch Foundation [I-1733]
- Howard Hughes Medical Institute (Faculty Scholars Program)
- Cancer Prevention and Research Institute of Texas [RP160089]
- Robert L. Moody, Sr. Faculty Scholar award
- Joel B. Steinberg Chair in Pediatrics
- Tsinghua University [53332200517]
- National Science and Technology Major Project for Significant New Drug Development [2017ZX09304015]
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- University of Texas Specialized Programs of Research Excellence (SPORE) [P50CA70907]
- ACS Research Scholar Award [RSG-13-300-01-TBG]
- Damon Runyon Cancer Research Foundation [DRR-26-13]
- [SCLC U24 CA213274]
- NATIONAL CANCER INSTITUTE [R35CA220449, U24CA213274, R01CA187457, P50CA070907, U01CA213338] Funding Source: NIH RePORTER
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)/MYCHigh SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.
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