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

Gurkan Mollaoglu; Matthew R Guthrie; Stefanie Böhm; Johannes Brägelmann; Ismail Can; Paul M Ballieu; Annika Marx; Julie George; Christine Heinen; Milind D Chalishazar; Haixia Cheng; Abbie S Ireland; Kendall E Denning; Anandaroop Mukhopadhyay; Jeffery M Vahrenkamp; Kristofer C Berrett; Timothy L Mosbruger; Jun Wang; Jessica L Kohan; Mohamed E Salama; Benjamin L Witt; Martin Peifer; Roman K Thomas; Jason Gertz; Jane E Johnson; Adi F Gazdar; Robert J Wechsler-Reya; Martin L Sos; Trudy G Oliver

doi:10.1016/j.ccell.2016.12.005

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

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

Authors

Gurkan Mollaoglu¹, Matthew R Guthrie¹, Stefanie Böhm², Johannes Brägelmann², Ismail Can¹, Paul M Ballieu¹, Annika Marx², Julie George³, Christine Heinen³, Milind D Chalishazar¹, Haixia Cheng¹, Abbie S Ireland¹, Kendall E Denning¹, Anandaroop Mukhopadhyay¹, Jeffery M Vahrenkamp¹, Kristofer C Berrett¹, Timothy L Mosbruger⁴, Jun Wang⁵, Jessica L Kohan⁶, Mohamed E Salama⁶, Benjamin L Witt⁶, Martin Peifer⁷, Roman K Thomas⁸, Jason Gertz¹, Jane E Johnson⁹, Adi F Gazdar¹⁰, Robert J Wechsler-Reya⁵, Martin L Sos¹¹, Trudy G Oliver¹²

Affiliations

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.

Publication types

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

MeSH terms

Animals
Aurora Kinases / antagonists & inhibitors*
Basic Helix-Loop-Helix Transcription Factors / physiology
Disease Progression
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / etiology
Mice
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins c-myc / physiology*
Small Cell Lung Carcinoma / drug therapy*
Small Cell Lung Carcinoma / etiology

Substances

Basic Helix-Loop-Helix Transcription Factors
MYC protein, human
NEUROD1 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Aurora Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding