Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 2, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201910852
Keywords
APR‐ 246; Eprenetapopt; glutathione; MRP1; p53
Categories
Funding
- Swedish Research Council (Vetenskapsradet)
- Swedish Cancer Society (Cancerfonden)
- Swedish Childhood Cancer Fund (Barncancerfonden)
- Radiumhemmets Forskningsfonder
- Knut and Alice Wallenberg Foundation
- Aprea Therapeutics
- National Health and Medical Research Council (NMHRC) [APP1120293]
- Department of Health and Human Services acting through the Victorian Cancer Agency, Victoria, Australia [MCRF16002]
- Tour de Cure Foundation
- National Health and Medical Research Council of Australia [GNT1164081]
- Medical Research Council [RG84369]
- Cancer Research UK [RG81771/84119]
- Australian Cancer Research Foundation (ACRF)
- Phenomics Australia (PA) through Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program
- Peter MacCallum Cancer Centre Foundation
- University of Melbourne Research Collaborative Infrastructure Program (MCRIP)
- Karolinska Institutet
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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.
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.
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