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  • p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism.

p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism.

Nature communications (2023-07-22)
Jonuelle Acosta, Qinglan Li, Nelson F Freeburg, Nivitha Murali, Alexandra Indeglia, Grant P Grothusen, Michelle Cicchini, Hung Mai, Amy C Gladstein, Keren M Adler, Katherine R Doerig, Jinyang Li, Miguel Ruiz-Torres, Kimberly L Manning, Ben Z Stanger, Luca Busino, Maureen Murphy, Liling Wan, David M Feldser
ABSTRACT

The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.

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