Bebber, Christina M., Thomas, Emily S., Stroh, Jenny, Chen, Zhiyi, Androulidaki, Ariadne, Schmitt, Anna, Hoehne, Michaela N., Stueker, Lukas, Alves, Cleidson de Padua, Khonsari, Armin, Dammert, Marcel A., Parmaksiz, Fatma, Tumbrink, Hannah L., Beleggia, Filippo ORCID: 0000-0003-0234-7094, Sos, Martin L., Riemer, Jan, George, Julie, Brodesser, Susanne, Thomas, Roman K., Reinhardt, H. Christian and von Karstedt, Silvia (2021). Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Nat. Commun., 12 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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Abstract

Loss of TP53 and RB1 in treatment-naive small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naive SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naive SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling. While NE SCLC is ferroptosis resistant, it acquires selective addiction to the TRX anti-oxidant pathway. In experimental settings of non-NE/NE intratumoral heterogeneity, non-NE or NE populations are selectively depleted by ferroptosis or TRX pathway inhibition, respectively. Preventing subtype plasticity observed under single pathway targeting, combined treatment kills established non-NE and NE tumors in xenografts, genetically engineered mouse models of SCLC and patient-derived cells, and identifies a patient subset with drastically improved overall survival. These findings reveal cell death pathway mining as a means to identify rational combination therapies for SCLC. The high degree of subtype plasticity in small cell lung cancer (SCLC) poses a therapeutic challenge. Here, the authors show that the non-neuroendocrine (non-NE) subtype of SCLC is sensitive to ferroptosis while the neuroendocrine (NE) subtype is vulnerable to TRX anti-oxidant pathway inhibition, and the combination of these two treatments in SCLC circumvents non-NE/NE subtype plasticity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bebber, Christina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Emily S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroh, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, ZhiyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Androulidaki, AriadneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, Michaela N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stueker, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alves, Cleidson de PaduaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khonsari, ArminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parmaksiz, FatmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemer, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
George, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Karstedt, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-592828
DOI: 10.1038/s41467-021-22336-4
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MIXED LINEAGE KINASE; LIPID-METABOLISM; DOMAIN-LIKE; IDENTIFICATION; DEATH; TRAIL; INACTIVATION; GLUTATHIONE; EXPRESSION; CASPASE-8Multiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59282

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