Dammed, Marcel A., Bragelmann, Johannes, Olsen, Rachelle R., Boehm, Stefanie, Monhasery, Niloufar, Whitney, Christopher P., Chalishazar, Milind D., Tumbrink, Hannah L., Guthrie, Matthew R., Klein, Sebastian, Irelands, Abbie S., Ryan, Jeremy, Schmitt, Anna, Marx, Annika, Ozretic, Luka, Castiglione, Roberta ORCID: 0000-0002-9828-4405, Lorenz, Carina, Jachimowicz, Ron D., Wolf, Elmar ORCID: 0000-0002-5299-6335, Thomas, Roman K., Poirier, John T., Buettner, Reinhard, Sen, Triparna, Byers, Lauren A., Reinhardt, H. Christian, Letai, Anthony, Oliver, Trudy G. and Sos, Martin L. (2019). MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dammed, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bragelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olsen, Rachelle R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehm, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monhasery, NiloufarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whitney, Christopher P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chalishazar, Milind D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guthrie, Matthew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Irelands, Abbie S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryan, JeremyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marx, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Castiglione, RobertaUNSPECIFIEDorcid.org/0000-0002-9828-4405UNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jachimowicz, Ron D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, ElmarUNSPECIFIEDorcid.org/0000-0002-5299-6335UNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poirier, John T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sen, TriparnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Byers, Lauren A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Letai, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliver, Trudy G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-144864
DOI: 10.1038/s41467-019-11371-x
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AURORA KINASE; DNA-DAMAGE; ALISERTIB; THERAPYMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14486

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