A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.

Automated summary

The tumor suppressor gene TP53 is commonly mutated in cancer, and the compound APR-246 shows promise in targeting mutant p53 protein for cancer therapy. Combining APR-246 with inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, particularly in TP53 mutant cells, indicating the importance of redox homeostasis in response to mutant p53-targeted therapy.