Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer.
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.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Dong-Wook
DW
Kim
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;
Nan
N
Wu
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida 33612, USA;
Young-Chul
YC
Kim
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
Pei Feng
PF
Cheng
Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
Ryan
R
Basom
Stanford University Institute for Stem Cell Biology and Regenerative Medicine, Palo Alto, California 94305, USA;
Dongkyoon
D
Kim
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Colin T
CT
Dunn
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Anastasia Y
AY
Lee
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Keebeom
K
Kim
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Chang Sup
CS
Lee
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Andrew
A
Singh
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;
Adi F
AF
Gazdar
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.
Chris R
CR
Harris
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
Robert N
RN
Eisenman
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA;
Kwon-Sik
KS
Park
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;
David
D
MacPherson
D000818:Animals; D030801:Animals, Genetically Modified; D052160:Benzothiazoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
D052160:Benzothiazoles; C557717:CX 5461; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D016271:Proto-Oncogene Proteins c-myc; D012318:RNA Polymerase I
neuroendocrine; oncogene; progression; ribosome biogenesis; transcription factor