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

Abstract

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.

• Authors: Sophia Ceder, Sofi E Eriksson, Emarndeena H Cheteh, Swati Dawar, Mariana Corrales Benitez, Vladimir J N Bykov, Kenji M Fujihara, Mélodie Grandin, Xiaodun Li, Susanne Ramm, Corina Behrenbruch, Kaylene J Simpson, Frédéric Hollande, Lars Abrahmsen, Nicholas J Clemons, Klas G Wiman
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 13 Issue 2 Pg. e10852 (02 05 2021) ISSN: 1757-4684 [Electronic] England
• PMID: 33314700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Pharmaceutical Preparations
• Quinuclidines
• Sulfhydryl Compounds
• Tumor Suppressor Protein p53
• eprenetapopt

Topics

• Cell Death
• Cell Line, Tumor
• Humans
• Mutation
• Neoplasms (drug therapy)
• Pharmaceutical Preparations
• Quinuclidines
• Sulfhydryl Compounds
• Tumor Suppressor Protein p53 (genetics)