ELUCIDATING THE MOLECULAR DETERMINANTS OF P53-MEDIATED PLEIOTROPIC EFFECTS IN SMALL CELL LUNG CANCER
Small cell lung cancer (SCLC) is the most lethal subtype of lung cancer and comprises ~15% of all lung cancer cases. Together with the retinoblastoma (Rb) tumor suppressor, p53 is inactivated in the vast majority (>90%) of SCLC cases. p53 is a pleiotropic tumor suppressor gene that responds to a wide array of genotoxic and cellular stresses to effectuate diverse tumor suppressive programs such as activation of cell death and senescence. While loss of p53 function is widespread in SCLC, it is not well-understood how p53 mediates tumor suppression in this context. To address this knowledge gap, we utilized a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated. We identified that SCLC tumors maintain a requirement for p53 inactivation. Furthermore, we discovered tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces a canonical senescence response in a subset of tumors, while, in others, p53 induces a non-apoptotic form of cell death that culminates in necrosis. We pinpointed the cyclophilin family of peptidyl prolyl cis-trans isomerases as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines that are 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. This work demonstrates that a previously unappreciated intertumoral heterogeneity in SCLC can influence the biological response to p53 restoration, describes a novel mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.