Journal article

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

David SH Liu, Matthew Read, Carleen Cullinane, Walid J Azar, Christina M Fennell, Karen G Montgomery, Sue Haupt, Ygal Haupt, Klas G Wiman, Cuong P Duong, Nicholas J Clemons, Wayne A Phillips

GUT | BMJ PUBLISHING GROUP | Published : 2015

Abstract

OBJECTIVES: p53 is a critical tumour suppressor and is mutated in 70% of oesophageal adenocarcinomas (OACs), resulting in chemoresistance and poor survival. APR-246 is a first-in-class reactivator of mutant p53 and is currently in clinical trials. In this study, we characterised the activity of APR-246 and its effect on p53 signalling in a large panel of cell line xenograft (CLX) and patient-derived xenograft (PDX) models of OAC. DESIGN: In vitro response to APR-246 was assessed using clonogenic survival, cell cycle and apoptosis assays. Ectopic expression, gene knockdown and CRISPR/Cas9-mediated knockout studies of mutant p53 were performed to investigate p53-dependent drug effects. p53 sig..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia Centres for Research Excellence grant


Funding Acknowledgements

This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Centres for Research Excellence grant (1040947) (WAP) and a Peter MacCallum Research Foundation New Investigator grant (DL). DL was supported by the John Loewenthal, Reg Worcester and Eric Bishop Research Fellowships through the Royal Australasian College of Surgeons (RACS) Foundation for Surgery and an Australian Postgraduate Research award from the NHMRC. MR was supported by the Thornell-Shore Memorial scholarship from the RACS and the Sir Thomas Naghten Fitzgerald Scholarship from The University of Melbourne. Some tissue samples used in this project were provided by the Victorian Cancer Biobank with appropriate ethics approval. The Victorian Cancer Biobank is supported by the Victorian Government, Australia.