Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• The TP53 gene is frequently mutated in various cancers, leading to diverse gain-of-function effects.
• Targeting mutant p53 is challenging due to the variety of TP53 mutations.
• The compound NSC59984 shows promise in restoring wild-type p53 activity in cancer cells.

Purpose of the Study:

• To investigate the effects of NSC59984 on esophageal adenocarcinoma cells with specific TP53 mutations.
• To elucidate the impact of NSC59984 on p53 transcriptional regulation and cellular metabolism.
• To determine if NSC59984 efficacy varies based on specific TP53 mutation status.

Main Methods:

• Treatment of esophageal adenocarcinoma cells with NSC59984.
• Analysis of p53 transcriptional activity and apoptosis induction.
• Metabolic profiling, including pentose phosphate pathway and glycolysis assessment.
• Measurement of reactive oxygen species (ROS) and glutathione levels.

Main Results:

• NSC59984 reactivated p53 transcriptional regulation and induced mitochondrial intrinsic apoptosis.
• Metabolic analysis revealed increased pentose phosphate pathway utilization and inhibited glycolysis.
• NSC59984 increased ROS production and decreased glutathione levels, with enhanced effects when combined with buthionine sulfoximine.
• The compound demonstrated substantially greater efficacy in cells harboring the p53 R248W mutation.

Conclusions:

• NSC59984 exerts p53-dependent effects on cellular metabolism and induces apoptosis in esophageal adenocarcinoma.
• The efficacy of NSC59984 is significantly influenced by the specific TP53 mutation, particularly R248W.
• Cancer treatment strategies for TP53-driven cancers should consider individual mutational status for a patient-centric approach.