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Cancer Cell. 2017 Feb 13;31(2):270-285. doi: 10.1016/j.ccell.2016.12.005. Epub 2017 Jan 12.

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition.

Author information

1
Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
2
Molecular Pathology, Institute for Pathology, Medical Faculty, University of Cologne, 50937 Cologne, Germany; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
3
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
4
Huntsman Cancer Institute, Bioinformatics Shared Resource, Salt Lake City, UT 84112, USA.
5
Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
6
Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84112, USA.
7
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
8
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany; Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
9
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
10
Department of Pathology, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75235, USA.
11
Molecular Pathology, Institute for Pathology, Medical Faculty, University of Cologne, 50937 Cologne, Germany; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Electronic address: martin.sos@uni-koeln.de.
12
Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA. Electronic address: trudy.oliver@hci.utah.edu.

Abstract

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.

KEYWORDS:

ASCL1; Aurora kinase inhibitor; MYC; NEUROD1; chemotherapy; genetically engineered mouse model; neuroendocrine; small-cell lung cancer

PMID:
28089889
PMCID:
PMC5310991
DOI:
10.1016/j.ccell.2016.12.005
[Indexed for MEDLINE]
Free PMC Article

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