Inhibiting the system xC−/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 xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC− 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 biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…Likewise, direct depletion of cystine from plasma using an engineered cystine-degrading enzyme conjugate ( i.e., cyst(e)inase) arrests tumor growth and triggers cell death (Cramer et al, 2017). Agents that conjugate to glutathione, such as APR-246, as well as chemical or genetic inhibition of glutathione biosynthesis, disrupt tumor cell growth and induce a ferroptosis-like form of cell death (Liu et al, 2017). Typically, elevated levels of ROS are detected in response to perturbation of cysteine or glutathione metabolism and, where tested, cell death is prevented by antioxidant treatment.…”

Molecular mechanisms of ferroptosis and its role in cancer therapy

“…P53 is a tumour suppressor gene that is activated under different stress stimuli. P53 is involved in ferroptosis as a transcriptional repressor of SLC7A11, impairing cysteine import and promoting ferroptosis initiation . P53 is also involved in other programmed cell death processes.…”

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

“…In a recent study, Sato et al () showed that erastin, a ferroptosis (regulated necrotic cell death) inducer, synergized with cisplatin to increase its cytotoxicity in cancer cells via irreversible inhibition of Sx c − . In yet another interesting study, Liu et al () and Clemons, Liu, Duong, and Phillips () discussed the importance of therapeutic strategies for targeting mutant p53 protein. One such strategy involved suppressing function of xCT along with APR‐246, a small‐molecule known to restore sequence‐specific DNA binding of mutant p53 resulting in wild‐type p53 transcriptional activity and tumor‐suppressor function.…”

“…. In yet another interesting study, Liu et al (2017) and Clemons, Liu, Duong, and Phillips (2017) and investigated the role of activating transcription factor 4 (ATF4) which critically regulates the oxido-metabolic state in gliomas in the pathogenesis of temozolomide (TMZ) (first-line treatment for malignant gliomas)-resistance. The authors found out that the TMZ treatment led to increased expression of ATF4, xCT among others and the elevation of xCT as a consequential event of ATF4 activation.…”