Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer

  1. David MacPherson2,3,15
  1. 1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
  2. 2Division of human Biology, Fred Hutchinson Cancer Research Center,Seattle,Washington 98109, USA;
  3. 3Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
  4. 4Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida 33612, USA;
  5. 5Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
  6. 6Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
  7. 7Stanford University Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, California 94305, USA;
  8. 8Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  9. 9Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  10. 10Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
  11. 11Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey 08901, USA;
  12. 12Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA;
  13. 13Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA
  1. Corresponding authors: dmacpher{at}fhcrc.org, kp5an{at}virginia.edu

  1. ↵14 These authors contributed equally to this work.

  2. ↵15 These authors contributed equally to this work.

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.

Keywords

Footnotes

  • Received February 10, 2016.
  • Accepted May 5, 2016.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. doi: 10.1101/gad.279307.116 Genes & Dev. 30: 1289-1299 © 2016 Kim et al.; Published by Cold Spring Harbor Laboratory Press

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