Journal article

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

Sophia Ceder, Sofi E Eriksson, Emarndeena H Cheteh, Swati Dawar, Mariana Corrales Benitez, Vladimir JN Bykov, Kenji M Fujihara, Melodie Grandin, Xiaodun Li, Susanne Ramm, Corina Behrenbruch, Kaylene J Simpson, Frederic Hollande, Lars Abrahmsen, Nicholas J Clemons, Klas G Wiman

EMBO MOLECULAR MEDICINE | WILEY | Published : 2020

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 ..

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Grants

Awarded by National Health and Medical Research Council (NMHRC)


Awarded by Department of Health and Human Services acting through the Victorian Cancer Agency, Victoria, Australia


Awarded by National Health and Medical Research Council of Australia


Awarded by Medical Research Council


Awarded by Cancer Research UK


Funding Acknowledgements

This work was supported by research grants to K.G.W. from the Swedish Research Council (Vetenskapsradet), the Swedish Cancer Society (Cancerfonden), the Swedish Childhood Cancer Fund (Barncancerfonden), Radiumhemmets Forskningsfonder, Knut and Alice Wallenberg Foundation, Aprea Therapeutics and Karolinska Institutet, and by a National Health and Medical Research Council (NMHRC) Project Grant #APP1120293 and a Fellowship (MCRF16002) from the Department of Health and Human Services acting through the Victorian Cancer Agency, Victoria, Australia, to N.J.C.. F.H. is supported by a Senior Research Grant from the Tour de Cure Foundation and a Project Grant from the National Health and Medical Research Council of Australia (GNT1164081). We thank Rebecca Fitzgerald (R.C.F.) for her generous funding of the eso-PDO experiments. R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). Sample collection for organoid generation was funded by a program grant to R.C.F. from Cancer Research UK (RG81771/84119). The Victorian Centre for Functional Genomics (K.J.S.) is funded by the Australian Cancer Research Foundation (ACRF), Phenomics Australia (PA) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program, the Peter MacCallum Cancer Centre Foundation and the University of Melbourne Research Collaborative Infrastructure Program (MCRIP). We thank Susan Cole for sharing the MRP1k-pcDNA3.1(-) and relevant plasmids, and Styrbjorn Bystrom (Aprea Therapeutics) for valuable advice on the reversible nature of MQ conjugation. We are grateful for the technical advice concerning <SUP>14</SUP>C measurements from Kristina Witt (Karolinska Institutet). We thank Peter Chumakov (Engelhardt Institutet of Molecular Biology) for H1299 cells, Bert Vogelstein (Johns Hopkins Oncology Center) for HCT116 cells, and Rolf Kiessling (Karolinska Institutet) for KADA cells. Finally, we thank Lars-Gunnar Larsson (Karolinska Institutet) for whole exome sequencing and former laboratory member Fredrik Jerhammar for culturing ESTDAB-140, ESTDAB-037, ESTDAB-049, SKMEL-2, and A375 cells. Where indicated, analyses were based on data generated from the TCGA Research Network: .