A thiol‐bound drug reservoir enhances APR‐246‐induced mutant p53 tumor cell death
Open Access
- 14 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 13 (2), e10852
- https://doi.org/10.15252/emmm.201910852
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.Keywords
Funding Information
- Vetenskapsrådet (2017‐01509)
- Cancerfonden (18 0774)
- Barncancerfonden (PR2017‐0106)
- Radiumhemmets Forskningsfonder (171213)
- Knut och Alice Wallenbergs Stiftelse
- Karolinska Institutet
- National Health and Medical Research Council (APP1120293, GNT1164081)
- Department of Health and Human Services, State Government of Victoria (MCRF16002)
- Medical Research Council (RG84369)
- Australian Cancer Research Foundation
- Cancer Research UK (RG81771/84119)
This publication has 77 references indexed in Scilit:
- Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53Nature Communications, 2013
- Clinicopathological Impact of ABCC1/MRP1 and ABCC4/MRP4 in Epithelial Ovarian CarcinomaBioMed Research International, 2013
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasisBritish Journal of Cancer, 2010
- Extracellular thiol-assisted selenium uptake dependent on the x c − cystine transporter explains the cancer-specific cytotoxicity of seleniteProceedings of the National Academy of Sciences, 2009
- PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core DomainCancer Cell, 2009
- The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.Clinical Cancer Research, 2006
- Substrate recognition and transport by multidrug resistance protein 1 (ABCC1)FEBS Letters, 2005
- PRIMA-1MET synergizes with cisplatin to induce tumor cell apoptosisOncogene, 2005
- Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compoundNature Medicine, 2002