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. SalamaBenjamin 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

Research output: Contribution to journalArticle

111 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)270-285
Number of pages16
JournalCancer cell
Volume31
Issue number2
DOIs
StatePublished - Feb 13 2017

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Mollaoglu, G., Guthrie, M. R., Böhm, S., Brägelmann, J., Can, I., Ballieu, P. M., Marx, A., George, J., Heinen, C., Chalishazar, M. D., Cheng, H., Ireland, A. S., Denning, K. E., Mukhopadhyay, A., Vahrenkamp, J. M., Berrett, K. C., Mosbruger, T. L., Wang, J., Kohan, J. L., ... Oliver, T. G. (2017). MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer cell, 31(2), 270-285. https://doi.org/10.1016/j.ccell.2016.12.005