Tumor addiction to late p53 inactivation
Final Report Abstract
The addiction of tumors to oncogenes is well-established and provides the rationale for oncogene-targeted therapies, but it is less clear whether tumors depend on the absence of tumor suppressors. This has been studied for p53 – the most commonly inactivated tumor suppressor. Mouse with p53 allele that can be switched from knockout to wildtype have provided first genetic proof-of-concept that restoring p53 function induces therapeutic responses. However, tumor development in a p53-null background abrogates the need for additional mutations in p53- dependent pathways such as oncogene-induced apoptosis or senescence. Reactivation of p53 in this context restores coupling of oncogenic signals to intact apoptosis or senescence machineries and results in tumor regression. In humans, p53 mutations in sporadic cancer often occur at later stages of tumorigenesis. Such tumors initially evolve in the presence of wild-type p53 and acquire alterations in the p53 pathway. If such tumors mutate p53 later, the preexisting alterations in the p53 pathway could limit the therapeutic efficacy of p53 reactivation. Some compounds targeted to reactivate p53 were evaluated in clinical trials, which showed that observed therapeutic effects are sometimes explained by off-target activities. In addition, many of the compounds fail to fully reactivate mutant p53 proteins, raising the question how much of p53 activity is sufficient to provide therapeutic effects. The goals of this project were to evaluate whether tumors become dependent on the late-stage loss of p53, and to test if partial reactivation of p53 is sufficient to provide significant response. In the first part of the study we genetically modeled late-stage p53 inactivation and therapeutic reactivation in mouse Myc-driven lymphoma and human tumor cells using the reversibly switchable p53ERTAM. Our results confirmed that ARF alterations prevent a p53 reactivation response in tumor cells with late-stage p53 inactivation as predicted. However, Myc-lymphoma that down-regulated ARF during tumor development restored ARF expression upon p53ERTAM inactivation and thereby became susceptible to p53 reactivation. Our findings show that tumor cells that have evolved in the presence of active p53 can rapidly adapt and become addicted to p53 inactivation. In addition, it indicates that ARF expression in tumors with late stage p53 mutations could serve as a potential biomarker for predicting p53 reactivation responses. In the second part we genetically modelled partial p53 reactivation using knock-in mice with inducible expression of the p53 variant E177R in different transplanted and autochthonous mouse models of acute myeloid leukemia and B or T cell lymphoma. We show that p53-deficient cancer cells proved to be so addicted to the absence of p53 that even the low-level activity of E177R is detrimental to cancer growth. These studies provide fundamental support for p53 as a suitable target for therapeutic reactivation strategies.
Publications
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Loss of p53 function at late stages of tumorigenesis confers ARF-dependent vulnerability to p53 reactivation therapy. Proceedings of the National Academy of Sciences, 116(44), 22288-22293.
Klimovich, Boris; Mutlu, Samet; Schneikert, Jean; Elmshäuser, Sabrina; Klimovich, Maria; Nist, Andrea; Mernberger, Marco; Timofeev, Oleg & Stiewe, Thorsten
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p53 partial loss-of-function mutations sensitize to chemotherapy. Oncogene, 41(7), 1011-1023.
Klimovich, Boris; Merle, Nastasja; Neumann, Michelle; Elmshäuser, Sabrina; Nist, Andrea; Mernberger, Marco; Kazdal, Daniel; Stenzinger, Albrecht; Timofeev, Oleg & Stiewe, Thorsten
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Partial p53 reactivation is sufficient to induce cancer regression. Journal of Experimental & Clinical Cancer Research, 41(1).
Klimovich, Boris; Meyer, Laura; Merle, Nastasja; Neumann, Michelle; König, Alexander M.; Ananikidis, Nikolaos; Keber, Corinna U.; Elmshäuser, Sabrina; Timofeev, Oleg & Stiewe, Thorsten
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“Partial loss-of-function p53 mutant fails to suppress tumorigenesis but responds to chemotherapy and induces tumor regression upon re-expression in p53-null cancer”, Abstract at the 10th UCT Science Day, Frankfurt, 2022
Oleg Timofeev, Nastasia Merle, Michelle Neumann & Thorsten Stiewe
