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

• Published in: Nature communications Vol. 10; no. 1; pp. 3485 - 11
• Main Authors: Dammert, Marcel A., Brägelmann, Johannes, Olsen, Rachelle R., Böhm, Stefanie, Monhasery, Niloufar, Whitney, Christopher P., Chalishazar, Milind D., Tumbrink, Hannah L., Guthrie, Matthew R., Klein, Sebastian, Ireland, Abbie S., Ryan, Jeremy, Schmitt, Anna, Marx, Annika, Ozretić, Luka, Castiglione, Roberta, Lorenz, Carina, Jachimowicz, Ron D., Wolf, Elmar, Thomas, Roman K., Poirier, John T., Büttner, Reinhard, Sen, Triparna, Byers, Lauren A., Reinhardt, H. Christian, Letai, Anthony, Oliver, Trudy G., Sos, Martin L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-08-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 38/15; 38/39; 49/91; 631/1647/1511; 631/67/1059/602; 631/67/1612/2143; 631/67/395; 64/60; Activation; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Cell cycle; Cell Line, Tumor; Chemotherapy; CHK1 protein; CRISPR; CRISPR-Cas Systems - genetics; Dependence; Disease Models, Animal; DNA damage; DNA Damage - drug effects; DNA Damage - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genotoxicity; Genotypes; HEK293 Cells; Humanities and Social Sciences; Humans; Immune checkpoint; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Mapping; Mcl-1 protein; Mice; Molecular Targeted Therapy - methods; multidisciplinary; Myc protein; Priming; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11371-x

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.
The expression of oncogenic
MYC
paralogs in small cell lung cancer is mutually exclusive. In this study, the authors show that MYC, but not MYCN or MYCL, represses BCL2, resulting in cells that are uniquely sensitive to apoptosis, and find that CHK1 and AURKA inhibitors may be useful for treating these cancers.