TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence
Menée à partir de cellules prélevées sur 74 patients atteints d'un carcinome épidermoïde de la tête et du cou, à l'aide de lignées cellulaires et d'une xénogreffe orthotopique, cette étude montre que des mutations altérant la protéine p53 augmentent la résistance des cellules cancéreuses à la radiothérapie en inhibant le processus de sénescence induit par les rayonnements ionisants
Purpose: Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity. Experimental Design: Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using shRNA and over-expressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and ROS assays were performed. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model. Results: Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (p=0.03). Cell lines with disruptive mutations were significantly more radioresistant (p<0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-beta-gal staining, p21 expression, and release of reactive oxygen species (ROS). The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin. Conclusions: Disruptive TP53 mutations in HNSCC tumors predicts for LRR, due to increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.