Differential Efficacy Of P53 Restoration In Induction And Maintenance Of Senescence In Premalignant And Malignant Cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PARestoration of p53 in tumors has been suggested as a possible therapeutic approach, based on preclinical in vivo and in vitro evidence of possible efficacy. However, the relationship between the timing of p53 restoration and its efficacy is still unclear. We now show that restoration of p53 in murine pre-malignant proliferating pineal tumors results in effective cell cycle exit and induction of cellular senescence, while p53 reactivation in established malignant pineal tumors does not impact cell proliferation, unless paired with DNA damaging therapies. This differential effect was not related to levels of p19Arf expression, as its expression was more pronounced in malignant tumors, nor to MAPK pathway activity. Interestingly, in premalignant lesions induced to senesce by p53 restoration, inactivation of p53 after senescence resulted in re-entry into the cell cycle, and rapid tumor progression. These findings were also validated in cell culture models of Cyclin D1-induced and RasV12-induced senescence in murine pineal cells and mouse embryo fibroblasts, respectively. Evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET), of which pineoblastoma is a subtype, showed low activity of the p53 pathway, while only one of 6 tumors had p53 deletion or mutation. Together, this data shows that restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, where it may need to be paired with DNA damaging agents, to engage it in tumor suppression. Furthermore, p53 activation may need to be continually sustained for effective tumor suppression in such lesions undergoing senescence as a tumor suppressor mechanism. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene seems to be intact but the pathway inactive in the majority of examined tumors.Citation Format: Mohammad Harajly, Hassan Zalzali, Sandra Ghayad, Farrah Ghamloush, Mark Jabbour, Hussein Basma, Ayman Tawil, Zafar Nawaz, Raya H. Saab. Differential efficacy of p53 restoration in induction and maintenance of senescence in premalignant and malignant cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1227. doi:10.1158/1538-7445.AM2015-1227