Tumor addiction to late p53 inactivation

• Applicant: Professor Dr. Oleg Timofeev
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418075894

Cancer development is driven by activated oncogenes and loss of tumor suppressors. While the addiction of tumors to oncogenes is well-established and provides the rationale for oncogene-targeted therapies, it is less clear whether tumors likewise depend on the absence of tumor suppressors. This issue has been studied most extensively for p53 – the most commonly inactivated tumor suppressor gene. Mouse studies using p53 alleles that can be switched from knockout to wildtype have provided first genetic proof-of-concept that restoring p53 function in a p53-deficient tumor induces therapeutic responses and has fueled the development of compounds targeted to reactivate inactive p53. As first compounds are currently evaluated in clinical trials, it becomes evident that many of the observed effects are explained by off-target activities, warranting more sophisticated investigation into the dependence of tumors on p53-loss.It is a caveat of the initial mouse studies that p53 reactivation was investigated only in models where loss of p53 was the initiating driver of tumorigenesis. Tumor development in a p53-compromised background alleviates the requirement 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. While these studies nicely model tumor development in Li-Fraumeni patients with p53-germline mutations, p53 mutations in sporadic patient tumors 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 to cope non-mutated p53. If such tumors mutate p53 at later time points, the preexisting alterations in the p53 pathway could limit the therapeutic efficacy of p53 reactivation approaches.It is the goal of this project to evaluate whether tumors become dependent on the loss of p53 if it occurs at late stages of tumor development. These studies will be conducted in a model of Myc-driven lymphoma in which p53 is a well-established barrier to tumorigenesis. To mimic pharmacological p53 reactivation, we will employ a tamoxifen-regulated p53-fusion protein that allows p53 to be reversibly switched from active to inactive and back. Lymphomas with early and late p53 inactivation will be compared to explore how the timing of p53 inactivation during tumorigenesis influences the response to therapeutic p53 reactivation approaches. The obtained findings will be validated in an independent mouse model of lung cancer and in human cancer cells. These studies are expected to provide fundamental support for or against p53 as a suitable target for therapeutic reactivation strategies.

• DFG Programme: Research Grants