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Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer.
Genes Dev. 2016 06 01; 30(11):1289-99.GD

Abstract

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer.

Authors+Show Affiliations

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Division of human Biology, Fred Hutchinson Cancer Research Center,Seattle,Washington 98109, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida 33612, USA;Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;Stanford University Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, California 94305, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey 08901, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;Division of human Biology, Fred Hutchinson Cancer Research Center,Seattle,Washington 98109, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27298335

Citation

Kim, Dong-Wook, et al. "Genetic Requirement for Mycl and Efficacy of RNA Pol I Inhibition in Mouse Models of Small Cell Lung Cancer." Genes & Development, vol. 30, no. 11, 2016, pp. 1289-99.
Kim DW, Wu N, Kim YC, et al. Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes Dev. 2016;30(11):1289-99.
Kim, D. W., Wu, N., Kim, Y. C., Cheng, P. F., Basom, R., Kim, D., Dunn, C. T., Lee, A. Y., Kim, K., Lee, C. S., Singh, A., Gazdar, A. F., Harris, C. R., Eisenman, R. N., Park, K. S., & MacPherson, D. (2016). Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. Genes & Development, 30(11), 1289-99. https://doi.org/10.1101/gad.279307.116
Kim DW, et al. Genetic Requirement for Mycl and Efficacy of RNA Pol I Inhibition in Mouse Models of Small Cell Lung Cancer. Genes Dev. 2016 06 1;30(11):1289-99. PubMed PMID: 27298335.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer. AU - Kim,Dong-Wook, AU - Wu,Nan, AU - Kim,Young-Chul, AU - Cheng,Pei Feng, AU - Basom,Ryan, AU - Kim,Dongkyoon, AU - Dunn,Colin T, AU - Lee,Anastasia Y, AU - Kim,Keebeom, AU - Lee,Chang Sup, AU - Singh,Andrew, AU - Gazdar,Adi F, AU - Harris,Chris R, AU - Eisenman,Robert N, AU - Park,Kwon-Sik, AU - MacPherson,David, PY - 2016/02/10/received PY - 2016/05/05/accepted PY - 2016/6/15/entrez PY - 2016/6/15/pubmed PY - 2017/4/28/medline KW - neuroendocrine KW - oncogene KW - progression KW - ribosome biogenesis KW - transcription factor SP - 1289 EP - 99 JF - Genes & development JO - Genes Dev. VL - 30 IS - 11 N2 - Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer. SN - 1549-5477 UR - https://www.unboundmedicine.com/medline/citation/27298335/Genetic_requirement_for_Mycl_and_efficacy_of_RNA_Pol_I_inhibition_in_mouse_models_of_small_cell_lung_cancer_ L2 - http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=27298335 DB - PRIME DP - Unbound Medicine ER -