TY - JOUR
T1 - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
AU - Dammert, Marcel A.
AU - Brägelmann, Johannes
AU - Olsen, Rachelle R.
AU - Böhm, Stefanie
AU - Monhasery, Niloufar
AU - Whitney, Christopher P.
AU - Chalishazar, Milind D.
AU - Tumbrink, Hannah L.
AU - Guthrie, Matthew R.
AU - Klein, Sebastian
AU - Ireland, Abbie S.
AU - Ryan, Jeremy
AU - Schmitt, Anna
AU - Marx, Annika
AU - Ozretić, Luka
AU - Castiglione, Roberta
AU - Lorenz, Carina
AU - Jachimowicz, Ron D.
AU - Wolf, Elmar
AU - Thomas, Roman K.
AU - Poirier, John T.
AU - Büttner, Reinhard
AU - Sen, Triparna
AU - Byers, Lauren A.
AU - Reinhardt, H. Christian
AU - Letai, Anthony
AU - Oliver, Trudy G.
AU - Sos, Martin L.
N1 - Funding Information:
We thank Marek Franitza, Christian Becker, and Janine Altmüller (Cologne Center for Genomics, University of Cologne) for technical support and Katia Garbert, Christian Müller, and Graziella Bosco (University of Cologne) for assistance with data acquisition. We also thank members of the Oliver Laboratory for technical support, especially Ismail Can and Danny Soltero. T.G.O. was supported in part by the NIH NCI (R01CA187487 and R21CA216504), the American Lung Association (LCD-506758), and the Huntsman Cancer Institute from the NIH NCI (P30CA042014). This work was furthermore supported by the Deutsche Forschungsgemeinschaft (CRC1399 to R.B., R.K.T., H.C.R., M.L.S.; KFO-286/RP2, RE 2246/2-1, RE 2246/7-1 to H.C.R. and TH1386/3-1 to R.K.T., M.L.S.), the Bundesmi-nisterium für Bildung und Forschung (e:Med 01ZX1603A to H.C.R., R.B., R.K.T. and 01ZX1406 to M.L.S.), the German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative (EFRE-0800397 to H.C.R., R.B., R.K.T. and M.L.S.), the Else Kröner-Fresenius Stiftung (EKFS-2014-A06 and 2016_Kolleg.19 to H.C.R., R.C., R.D.J., S.K. and Memorial Grant 2018_EKMS.35 to J.B.), the Köln Fortune program (to A.M.), and the Deutsche Krebshilfe (70113041 to H.C.R., 70112888 to M.L.S. and 70113129 to C.L.). Additional funding was provided by the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program (to R.B.) and as part of the Small Cell Lung Cancer Genome Sequencing Consortium (109679 to R.K.T., R.B.).
Funding Information:
Competing interests: M.L.S. and R.K.T. are founders and shareholders of PearlRiver Bio. M.L.S. received a commercial research grant from Novartis. R.K.T. is a founder of NEO New Oncology GmbH, now part of Siemens Healthcare, and received consulting and lecture fees from Merck, Roche, Lilly, Boehringer Ingelheim, Astra-Zeneca, Daiichi-Sankyo, MSD, NEO New Oncology, Puma, and Clovis. H.C.R. received consulting and lecture fees from Abbvie, Astra-Zeneca, Vertex, and Merck and received research funding from Gilead Pharmaceuticals; R.B. is an employee of Targos Molecular Pathology. The other authors declare no competing interests.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071154577&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071154577&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-11371-x
DO - 10.1038/s41467-019-11371-x
M3 - Article
C2 - 31375684
AN - SCOPUS:85071154577
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3485
ER -