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Bebber, C.M., Thomas, E.S., Stroh, J., Chen, Z., Androulidaki, A., Schmitt, A., Höhne, M.N., Stüker, L., de Pádua Alves,C., Khonsari, A.,|...|,Beleggia, F., Sos, M.L., Riemer, J., George, J., Brodesser, S., Thomas, R.K., Reinhardt, H.C. & von Karstedt, S.

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


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.

Read more at Nature Communications volume 12, Article number: 2048