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

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: Dong-Wook Kim, Nan Wu, Young-Chul Kim, Pei Feng Cheng, Ryan Basom, Dongkyoon Kim, Colin T Dunn, Anastasia Y Lee, Keebeom Kim, Chang Sup Lee, Andrew Singh, Adi F Gazdar, Chris R Harris, Robert N Eisenman, Kwon-Sik Park, David MacPherson
• Journal: Genes & development (Genes Dev) Vol. 30 Issue 11 Pg. 1289-99 (06 01 2016) ISSN: 1549-5477 [Electronic] United States
• PMID: 27298335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2016 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• Benzothiazoles
• CX 5461
• Enzyme Inhibitors
• Naphthyridines
• Proto-Oncogene Proteins c-myc
• RNA Polymerase I

Topics

• Animals
• Animals, Genetically Modified
• Benzothiazoles (pharmacology)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Silencing
• Lung Neoplasms (enzymology, genetics, physiopathology)
• Mice
• Naphthyridines (pharmacology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Polymerase I (antagonists & inhibitors, metabolism)
• Ribosomes (metabolism)
• Small Cell Lung Carcinoma (enzymology, genetics, physiopathology)
• Tumor Burden (drug effects)
• Tumor Cells, Cultured