2. Academic Validation
  3. Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small-cell lung cancer

  • J Clin Invest. 2021 Jan 4;131(1):e139929. doi: 10.1172/JCI139929.
Fang Huang 1 2,  Kenneth E Huffman 3,  Zixi Wang 2,  Xun Wang 2,  Kailong Li 2,  Feng Cai 2,  Chendong Yang 2,  Ling Cai 2 4,  Terry S Shih 2,  Lauren G Zacharias 2,  Andrew Chung 2,  Qian Yang 5,  Milind D Chalishazar 6,  Abbie S Ireland 6,  C Allison Stewart 7,  Kasey Cargill 7,  Luc Girard 3,  Yi Liu 5,  Min Ni 2,  Jian Xu 2,  Xudong Wu 8,  Hao Zhu 2,  Benjamin Drapkin 9,  Lauren A Byers 7,  Trudy G Oliver 6,  Adi F Gazdar 3,  John D Minna 3,  Ralph J DeBerardinis 2 10
Affiliations

Affiliations

  • 1 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Children's Medical Center Research Institute.
  • 3 Hamon Center for Therapeutic Oncology Research, Departments of Internal Medicine and Pharmacology, and Simmons Comprehensive Cancer Center.
  • 4 Department of Population and Data Sciences, and.
  • 5 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 6 Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
  • 7 Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 8 Department of Cell Biology, Tianjin Medical University, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin, China.
  • 9 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 10 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
PMID: 33079728 DOI: 10.1172/JCI139929
Abstract

MYC stimulates both metabolism and protein synthesis, but how cells coordinate these complementary programs is unknown. Previous work reported that, in a subset of small-cell lung Cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here, we demonstrated that primary MYChi human SCLC tumors also contained abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH linked the metabolic and protein synthesis outputs of oncogenic MYC. Coexpression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functioned as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant MYChi SCLC.

Keywords

Intermediary metabolism; Lung cancer; Metabolism; Oncogenes; Oncology.

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