Inhibiting the system x_C^-/glutathione axis selectively targets cancers with mutant-p53 accumulation.

ABSTRACT: TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system x_C^-, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System x_C^- inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive bi

SUBMITTER: Liu DS 

PROVIDER: S-EPMC5379068 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature