MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis PMID: 35484422

ADC Targets in Oncology

2026-04-10

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

Nat Cancer. 2022 Apr;3(4):471-485. doi: 10.1038/s43018-022-00355-4.

Hamed Alborzinia ^# ¹ ² ³ , Andrés F Flórez ^# ⁴ ⁵ , Sina Kreth ^# ⁶ ⁷ , Lena M Brückner ^# ⁶ ⁷ , Umut Yildiz ⁸ ⁹ , Moritz Gartlgruber ⁶ ⁷ , Dorett I Odoni ¹⁰ ¹¹ , Gernot Poschet ¹² , Karolina Garbowicz ⁶ ⁷ , Chunxuan Shao ⁴ , Corinna Klein ⁸ ⁹ , Jasmin Meier ⁸ ⁹ , Petra Zeisberger ⁸ ⁹ , Michal Nadler-Holly ¹³ , Matthias Ziehm ¹³ , Franziska Paul ¹⁴ , Jürgen Burhenne ¹⁵ , Emma Bell ⁶ ⁷ , Marjan Shaikhkarami ¹⁶ , Roberto Würth ⁸ ⁹ , Sabine A Stainczyk ⁶ ⁷ , Elisa M Wecht ⁶ ⁷ , Jochen Kreth ⁶ ⁷ , Michael Büttner ¹² , Naveed Ishaque ¹⁷ , Matthias Schlesner ¹⁰ ¹¹ , Barbara Nicke ¹⁸ , Carlo Stresemann ¹⁹ , María Llamazares-Prada ²⁰ , Jan H Reiling ²¹ , Matthias Fischer ²² , Ido Amit ¹⁴ , Matthias Selbach ¹³ ²³ , Carl Herrmann ¹⁰ ²⁴ , Stefan Wölfl ¹⁶ , Kai-Oliver Henrich ⁶ ⁷ , Thomas Höfer ⁴ , Andreas Trumpp ⁸ ⁹ ²⁵ , Frank Westermann ²⁶ ²⁷

Affiliations

1. Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany. [email protected].
2. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany. [email protected].
3. Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany. [email protected].
4. Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany.
5. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
6. Hopp Children's Cancer Center, Heidelberg, Germany.
7. Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany.
8. Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
9. Division of Stem Cells and Cancer German Cancer Research Center and Center for Molecular Biology of the University of Heidelberg Alliance, Heidelberg, Germany.
10. Bioinformatics and Omics Data Analytics, German Cancer Research Center, Heidelberg, Germany.
11. Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany.
12. Metabolomics Core Technology Platform, University of Heidelberg, Heidelberg, Germany.
13. Proteome Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
14. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
15. Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
16. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
17. Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Digital Health Center, Berlin, Germany.
18. Target Discovery Technologies, Bayer AG, Berlin, Germany.
19. Research & Development, Pharmaceuticals Division, Bayer AG, Berlin, Germany.
20. Division of Cancer Epigenomics, German Cancer Research Center, Member of the German Center for Lung Research, Heidelberg, Germany.
21. Translational Research to AdvanCe Therapeutics and Innovation in ONcology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
22. Experimental Pediatric Oncology, Children's Hospital and Center for Molecular Medicine, Medical Faculty, University of Cologne, Cologne, Germany.
23. Charité-Universitätsmedizin Berlin, Berlin, Germany.
24. Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, Heidelberg, Germany.
25. German Cancer Consortium, Heidelberg, Germany.
26. Hopp Children's Cancer Center, Heidelberg, Germany. [email protected].
27. Division of Neuroblastoma Genomics, German Cancer Research Center, Heidelberg, Germany. [email protected].
# Contributed equally.

Abstract

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to Ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering Ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple Ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.