Despite the apparent heterogeneity of different cancers, functional inactivation of the p53 network is common to almost all. However, which signals are responsible for triggering p53 during evolution of any specific tumor cell type, when this happens, what the immediate consequences of such activation might be for each tumor cell and for the whole tumor, and whether such signals are retained by established cancers, all remain largely unknown. Nonetheless, these are considerations with a profound impact on how p53 function is disabled in specific tumors and how therapeutically effective p53 restoration might be in each tumor type. This latter is of immediate relevance with the advent of practicable pharmacological strategies for re-instating p53 function. We will use a unique mouse model in which endogenous p53 function can be reversibly toggled between inactive and functional states to explore the diversity of responses to p53 restoration in differing cancers. In Aim 1, we will use a single oncogenic mechanism (activated Ras) to explore how tumor tissue type influences the response to p53 restoration. In Aim 2, we will use homologous sporadic models of lung cancer driven respectively by Ras, Myc, or Ras and Myc together, to determine how the oncogenic lesion modifies the response to p53 restoration within a single tumor tissue type. In Aim 3, we will investigate whether and how p53-restoration therapy fails. Do tumors recurring after p53 restoration arise by regeneration from a p53-refractory progenitor population or by selection and outgrowth of resistant mutants, how does this vary with tumor tissue type, and how might such resistance be averted? To address these questions we will use our well-characterized switchable p53 E5-myc lymphoma model and extend the same investigative strategy into the Ras-induced solid tumor models employed in Aim 1. PUBLIC HEALTH RELEVANCE: Although different cancers are very diverse, almost all involve inactivation of the p53 pathway. Hence, restoration of p53 function in cancers may be a highly effective, generally applicable and tumor-selective therapeutic strategy. We have developed a unique switchable knock-in mouse that enables us to model p53 functional restoration in any tumor type in vivo. We will use this mouse to explore the therapeutic efficacy, utility and mechanism of action of p53 and how this is dictated by tumor type, providing a basis for optimizing p53 restoration in cancer treatment.