Cargando…

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 i...

Descripción completa

Detalles Bibliográficos
Autores principales: Bebber, Christina M., Thomas, Emily S., Stroh, Jenny, Chen, Zhiyi, Androulidaki, Ariadne, Schmitt, Anna, Höhne, Michaela N., Stüker, Lukas, de Pádua Alves, Cleidson, Khonsari, Armin, Dammert, Marcel A., Parmaksiz, Fatma, Tumbrink, Hannah L., Beleggia, Filippo, Sos, Martin L., Riemer, Jan, George, Julie, Brodesser, Susanne, Thomas, Roman K., Christian Reinhardt, H., von Karstedt, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024350/
https://www.ncbi.nlm.nih.gov/pubmed/33824345
http://dx.doi.org/10.1038/s41467-021-22336-4
Descripción
Sumario: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.