MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer PMID: 31375684

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2019 Aug 2;10(1):3485. doi: 10.1038/s41467-019-11371-x.

Marcel A Dammert ¹ ² ³ , Johannes Brägelmann ¹ ² ³ ⁴ , Rachelle R Olsen ⁵ , Stefanie Böhm ² ³ , Niloufar Monhasery ¹ ² ³ , Christopher P Whitney ⁵ , Milind D Chalishazar ⁵ , Hannah L Tumbrink ¹ ² ³ , Matthew R Guthrie ⁵ , Sebastian Klein ² ³ ⁴ ⁶ , Abbie S Ireland ⁵ , Jeremy Ryan ⁷ , Anna Schmitt ⁸ ⁹ , Annika Marx ¹ ² ³ , Luka Ozretić ¹⁰ , Roberta Castiglione ⁴ ⁶ , Carina Lorenz ¹ ² ³ , Ron D Jachimowicz ⁸ ⁹ , Elmar Wolf ¹¹ , Roman K Thomas ² , John T Poirier ¹² , Reinhard Büttner ⁶ , Triparna Sen ¹³ , Lauren A Byers ¹³ , H Christian Reinhardt ⁴ ⁸ ⁹ , Anthony Letai ⁷ , Trudy G Oliver ¹⁴ , Martin L Sos ¹⁵ ¹⁶ ¹⁷

Affiliations

1. Molecular Pathology, Institute of Pathology, University Hospital of Cologne, 50937, Cologne, Germany.
2. Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931, Cologne, Germany.
3. Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne, Germany.
4. Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, 50931, Cologne, Germany.
5. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
6. Institute of Pathology, University Hospital of Cologne, 50937, Cologne, Germany.
7. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
8. Department I of Internal Medicine, University Hospital of Cologne, 50931, Cologne, Germany.
9. Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, 50931, Cologne, Germany.
10. Department of Cellular Pathology, Royal Free Hospital, London, NW3 2QG, UK.
11. Theodor Boveri Institute, Biocenter, University of Würzburg, 97074, Würzburg, Germany.
12. Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
13. Department of Thoracic and Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA.
14. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. [email protected].
15. Molecular Pathology, Institute of Pathology, University Hospital of Cologne, 50937, Cologne, Germany. [email protected].
16. Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931, Cologne, Germany. [email protected].
17. Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne, Germany. [email protected].

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.