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Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

ABSTRACT: Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of cancer therapy.

SUBMITTER: Dr. Oleg Timofeev

PROVIDER: S-SCDT-EMBOJ-2019-102096 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS:This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant-specific residual transcriptional activity scores. RESULTS:Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4-3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7-5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7-3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8-2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). CONCLUSION:The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. FUNDING:Canadian Institutes of Health Research (no. 148556).

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Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

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