Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes

Christina M. Bebber, Emily S. Thomas, Jenny Stroh, Zhiyi Chen, Ariadne Androulidaki, Anna Schmitt, Michaela N. Höhne, Lukas Stüker, Cleidson Pádua Alves, Armin Khonsari, Marcel A. Dammert, Fatma Parmaksiz, Hannah L. Tumbrink, Filippo Beleggia, Martin L. Sos, Jan Riemer, Julie George, Susanne Brodesser, Roman K. Thomas, H. Christian Reinhardt and Silvia Karstedt ()
Additional contact information
Christina M. Bebber: University of Cologne
Emily S. Thomas: University of Cologne
Jenny Stroh: University of Cologne
Zhiyi Chen: University of Cologne
Ariadne Androulidaki: University of Cologne
Anna Schmitt: University of Cologne
Michaela N. Höhne: University of Cologne
Lukas Stüker: University of Cologne
Cleidson Pádua Alves: University of Cologne
Armin Khonsari: University of Cologne
Marcel A. Dammert: University of Cologne
Fatma Parmaksiz: University of Cologne
Hannah L. Tumbrink: University of Cologne
Filippo Beleggia: University Hospital of Cologne
Martin L. Sos: University of Cologne
Jan Riemer: University of Cologne
Julie George: University of Cologne
Susanne Brodesser: University of Cologne
Roman K. Thomas: University of Cologne
H. Christian Reinhardt: University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK partner site Essen)
Silvia Karstedt: University of Cologne

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Loss of TP53 and RB1 in treatment-naïve 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-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22336-4

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DOI: 10.1038/s41467-021-22336-4

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