Nature Communications (Jul 2023)

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,
  • David M. Feldser

DOI
https://doi.org/10.1038/s41467-023-40161-9
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 18

Abstract

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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.