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

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 and David M. Feldser ()
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Jonuelle Acosta: University of Pennsylvania
Qinglan Li: University of Pennsylvania
Nelson F. Freeburg: University of Pennsylvania
Nivitha Murali: University of Pennsylvania
Alexandra Indeglia: University of Pennsylvania
Grant P. Grothusen: University of Pennsylvania
Michelle Cicchini: University of Pennsylvania
Hung Mai: University of Pennsylvania
Amy C. Gladstein: University of Pennsylvania
Keren M. Adler: University of Pennsylvania
Katherine R. Doerig: University of Pennsylvania
Jinyang Li: University of Pennsylvania
Miguel Ruiz-Torres: University of Pennsylvania
Kimberly L. Manning: University of Pennsylvania
Ben Z. Stanger: University of Pennsylvania
Luca Busino: University of Pennsylvania
Maureen Murphy: University of Pennsylvania
Liling Wan: University of Pennsylvania
David M. Feldser: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40161-9

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