title: MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition.
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.
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Gurkan
authors.initials: G
authors.lastname: Mollaoglu
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Guthrie
authors.affiliation: 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.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Böhm
authors.affiliation: 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.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brägelmann
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Can
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ballieu
authors.affiliation: 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.
authors.forename: Annika
authors.initials: A
authors.lastname: Marx
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Heinen
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Milind D
authors.initials: MD
authors.lastname: Chalishazar
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Abbie S
authors.initials: AS
authors.lastname: Ireland
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Kendall E
authors.initials: KE
authors.lastname: Denning
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Anandaroop
authors.initials: A
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vahrenkamp
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Kristofer C
authors.initials: KC
authors.lastname: Berrett
authors.affiliation: Huntsman Cancer Institute, Bioinformatics Shared Resource, Salt Lake City, UT 84112, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Mosbruger
authors.affiliation: Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84112, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Kohan
authors.affiliation: Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84112, USA.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT 84112, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Witt
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: 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.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gertz
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.affiliation: 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.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.affiliation: Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA. Electronic address: trudy.oliver@hci.utah.edu.
authors.forename: Trudy G
authors.initials: TG
authors.lastname: Oliver
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000209:etiology
chemical_list: D064127:Aurora Kinases; D051792:Basic Helix-Loop-Helix Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C489427:MYC protein, human; C093970:NEUROD1 protein, human
keywords: ASCL1; Aurora kinase inhibitor; MYC; NEUROD1; chemotherapy; genetically engineered mouse model; neuroendocrine; small-cell lung cancer