Publikationsserver der Universitätsbibliothek Marburg

Titel:Exploring mutant p53 targeting strategies for cancer therapy
Autor:Klimovich, Boris
Weitere Beteiligte: Timofeev, Oleg (PD Dr. )
Veröffentlicht:2020
URI:https://archiv.ub.uni-marburg.de/diss/z2020/0035
URN: urn:nbn:de:hebis:04-z2020-00358
DOI: https://doi.org/10.17192/z2020.0035
DDC:610 Medizin
Titel (trans.):Untersuchen von verschiedenen Strategien zum Targeting von mutiertem p53 für die Krebstherapie
Publikationsdatum:2020-02-04
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:

Summary:
TP53 is an essential tumor suppressor gene. It is inactivated in 50% of tumors, most frequently by missense mutations that result in the expression of a mutant p53 protein (mutp53). Mutp53 loses the ability to activate tumor-suppressive target genes and acquires pro-tumorigenic gain-of-function properties. An emerging strategy for treatment of cancers with missense p53 mutations is pharmacological restoration of wild-type p53 activity. Initial evidence that p53 reactivation leads to tumor regression was obtained in mouse models where p53 loss was the initiating event. Many patient tumors, however, develop in the presence of wild-type p53 and inactivate it only at later stages of evolution. To bypass p53-dependent tumor suppression such tumors acquire alterations in the p53 pathway that, in principle, could render p53 reactivation inefficient. To test this, we have modeled late-stage p53 inactivation in mice. Surprisingly restoration of p53 in such late-inactivated tumors resulted in widespread apoptosis and superior survival of the animals. ARF gene alterations were identified as a cause of primary or acquired resistance that could be overcome by Mdm2 inhibitors. Together this study provided proof of concept that p53 reactivation is an effective therapy option for tumors with late-stage p53 inactivation and identified ARF as a predictive biomarker. Among the many different missense mutations, cooperativity mutations represent a mechanistically unique class that often results in a partial loss-of-function (pLOF). As pLOF is a characteristic of many non-hotspot p53 mutations, we have tested if residual functions of two distinct p53 cooperativity mutants (p53E177R “RR” and p53R178E “EE”) may be exploited to induce cell death. Using embryonic development as a model, we have shown that Mdm2-deficiency results in constitutive stabilization of p53 cooperativity mutants and triggers massive apoptosis and embryonic lethality. This indicated that the apoptosis deficiency, characteristic for p53 pLOF mutants, can be rescued by inhibition of Mdm2. Studies of p53 cooperativity mutant mice confirmed that stabilization of mutp53 by pharmacological or constitutive Mdm2 inhibition lowers the apoptotic threshold, sensitizes tumor cells to the pro-apoptotic activity of DNA damaging drugs, and generates a survival benefit under chemotherapy. This was even seen for the DNA binding-deficient cooperativity mutant EE, pointing at a critical role of non-transcriptional apoptotic functions in the context of chemotherapy. In parallel, p53EE was found to be incapable of suppressing tumor development, highlighting a differential role of p53’s non-transcriptional apoptotic functions in tumor suppression and cancer therapy. Collectively, our investigation of two cooperativity mutants suggests that non-hot-spot p53 variants retain residual wild-type activities, that can be harnessed for cancer therapy.


* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten