Loss of p53 function at late stages of tumorigenesis confers ARF-dependent vulnerability to p53 reactivation therapy
Menée à l'aide d'un modèle murin de lymphome, cette étude démontre que l'inactivation tardive de la protéine p53 lors de la tumorigenèse confère aux cellules cancéreuses une sensibilité (dépendante de la protéine ARF) aux traitements destinés à réactiver la protéine p53
Mouse studies demonstrating regression of p53-null tumors following reinstatement of functional p53 have fueled the development of p53 reactivating drugs. However, successful p53 reactivation responses have only been formally demonstrated in tumor models where p53 inactivation served as the initiating event. Our study provides the first proof-of-principle evidence that p53 inactivation at late stages of tumorigenesis can also generate a vulnerability to p53 reactivation. However, this is dependent on intact ARF function highlighting ARF as a potential biomarker for p53 reactivation responses in tumors with late-stage p53 inactivation. It furthermore suggests the use of Mdm2 inhibitors as ARF mimetics for sensitizing ARF-deficient tumors to p53-reactivating drugs.Cancer development is driven by activated oncogenes and loss of tumor suppressors. While oncogene inhibitors have entered routine clinical practice, tumor suppressor reactivation therapy remains to be established. For the most frequently inactivated tumor suppressor p53, genetic mouse models have demonstrated regression of p53-null tumors upon p53 reactivation. While this was shown in tumor models driven by p53 loss as the initiating lesion, many human tumors initially develop in the presence of wild-type p53, acquire aberrations in the p53 pathway to bypass p53-mediated tumor suppression, and inactivate p53 itself only at later stages during metastatic progression or therapy. To explore the efficacy of p53 reactivation in this scenario, we used a reversibly switchable p53 (p53ERTAM) mouse allele to generate Eµ-Myc–driven lymphomas in the presence of active p53 and, after full lymphoma establishment, switched off p53 to model late-stage p53 inactivation. Although these lymphomas had evolved in the presence of active p53, later loss and subsequent p53 reactivation surprisingly activated p53 target genes triggering massive apoptosis, tumor regression, and long-term cure of the majority of animals. Mechanistically, the reactivation response was dependent on Cdkn2a/p19Arf, which is commonly silenced in p53 wild-type lymphomas, but became reexpressed upon late-stage p53 inactivation. Likewise, human p53 wild-type tumor cells with CRISPR-engineered switchable p53ERTAM alleles responded to p53 reactivation when CDKN2A/p14ARF function was restored or mimicked with Mdm2 inhibitors. Together, these experiments provide genetic proof of concept that tumors can respond, in an ARF-dependent manner, to p53 reactivation even if p53 inactivation has occurred late during tumor evolution.