MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Marcel A. Dammert, Johannes Brägelmann, Rachelle R. Olsen, Stefanie Böhm, Niloufar Monhasery, Christopher P. Whitney, Milind D. Chalishazar, Hannah L. Tumbrink, Matthew R. Guthrie, Sebastian Klein, Abbie S. Ireland, Jeremy Ryan, Anna Schmitt, Annika Marx, Luka Ozretić, Roberta Castiglione, Carina Lorenz, Ron D. Jachimowicz, Elmar Wolf, Roman K. Thomas, John T. Poirier, Reinhard Büttner, Triparna Sen, Lauren A. Byers, H. Christian Reinhardt, Anthony Letai, Trudy G. Oliver () and Martin L. Sos ()
Additional contact information
Marcel A. Dammert: University Hospital of Cologne
Johannes Brägelmann: University Hospital of Cologne
Rachelle R. Olsen: Huntsman Cancer Institute, University of Utah
Stefanie Böhm: University of Cologne
Niloufar Monhasery: University Hospital of Cologne
Christopher P. Whitney: Huntsman Cancer Institute, University of Utah
Milind D. Chalishazar: Huntsman Cancer Institute, University of Utah
Hannah L. Tumbrink: University Hospital of Cologne
Matthew R. Guthrie: Huntsman Cancer Institute, University of Utah
Sebastian Klein: University of Cologne
Abbie S. Ireland: Huntsman Cancer Institute, University of Utah
Jeremy Ryan: Harvard Medical School
Anna Schmitt: University Hospital of Cologne
Annika Marx: University Hospital of Cologne
Luka Ozretić: Royal Free Hospital
Roberta Castiglione: University Hospital Cologne
Carina Lorenz: University Hospital of Cologne
Ron D. Jachimowicz: University Hospital of Cologne
Elmar Wolf: University of Würzburg
Roman K. Thomas: University of Cologne
John T. Poirier: Memorial Sloan Kettering Cancer Center
Reinhard Büttner: University Hospital of Cologne
Triparna Sen: University of Texas, MD Anderson Cancer Center
Lauren A. Byers: University of Texas, MD Anderson Cancer Center
H. Christian Reinhardt: University Hospital Cologne
Anthony Letai: Harvard Medical School
Trudy G. Oliver: Huntsman Cancer Institute, University of Utah
Martin L. Sos: University Hospital of Cologne

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.

Date: 2019
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DOI: 10.1038/s41467-019-11371-x

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