1. Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes.
- Author
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Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Höhne MN, Stüker L, de Pádua Alves C, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, and von Karstedt S
- Subjects
- Animals, Antioxidants metabolism, Apoptosis, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Survival, Humans, Lipid Metabolism, Male, Mice, Nude, Models, Biological, Necroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Phospholipids metabolism, Prognosis, Thioredoxins metabolism, Mice, Ferroptosis, Neuroendocrine Tumors pathology, Small Cell Lung Carcinoma pathology
- 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.
- Published
- 2021
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