TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence

Abstract

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.

Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer

“…These results were confirmed in an independent cohort of patients (45). TP53 disruptive mutations also led to treatment failure through locoregional recurrence in HNSCC (46). In contrast with these studies, we found no association of TP53 disruptive mutations with a shorter OS in advanced NSCLC.…”

Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

“…[7][8][9][10][11][12][13][14][15][16][17][18][19]101 Although the demonstration of resistance to oncogenemediated targeted therapy through the adaptation of cellular metabolism suggests that the rewiring of cellular metabolism plays a fundamental, convergent role for oncogenes and signal transduction in promoting tumorigenesis, little is known about how the cancer signaling networks are remodeled and which pathways are invoked to sustain survival in the presence of drugs targeting central key signaling metabolic hubs (e.g., AMPK, mTOR) that respond to an array of signaling metabolic inputs and regulate a range of downstream effector metabolic pathways. Together, our current findings suggest, for the first time, that chronic adaptation to high doses of the AMPK agonist/mTOR inhibitor metformin appears to causally involve 2 highly intertwined molecular phenomena underlying enhanced cancer aggressiveness.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] While it might appear intuitive that deregulated cancer metabolism can activate pro-survival signaling and decrease druginduced apoptosis to provide a general, unspecific protection against cell injuries induced by multiple types of cytotoxicities, it is worth noting that resistance to oncogene-mediated targeted therapy has been shown to require a shift toward the very same metabolic state that is controlled by growth factor signaling. 20,21 In cancer cells sensitive to lapatinib, the small-molecule dual inhibitor of the oncogenes EGFR and HER2, receptor tyrosine kinase signaling is disrupted, and activity of its Ras, PI3K, and mTOR downstream effectors is abrogated; because oncogenedependent metabolic rewiring is prevented, cancer cell death is observed.…”

Statistical Analysis of Radiation-Induced Dynamics of Cancer Cell Transcriptome Using Dna-Microarray Data

“…Из литературных данных известно, что ТР53 мутантные раковые опухоли обладают высокой радиорезистентностью и устойчивостью к индукции апоптоза. Причины этого феномена до конца не ясны [18].…”