APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma. Issue 10 (17th July 2015)

• Record Type: Journal Article
• Authors: Liu, David S H; Read, Matthew; Cullinane, Carleen; Azar, Walid J; Fennell, Christina M; Montgomery, Karen G; Haupt, Sue; Haupt, Ygal; Wiman, Klas G; Duong, Cuong P; Clemons, Nicholas J; Phillips, Wayne A
• Is Part Of: Gut. Volume 64:Issue 10(2015)
• Page Start: 1506
• Page End: 1516
• Publication Date: 2015-07-17
• Subjects: OESOPHAGEAL CANCER -- ONCOGENES -- DRUG DEVELOPMENT; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-309770
• Languages: English
• ISSNs: 0017-5749

Abstract

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 signalling was examined using quantitative RT-PCR and western blot. Synergistic interactions between APR-246 and conventional chemotherapies were evaluated in vitro and in vivo using CLX and PDX models. Results: APR-246 upregulated p53 target genes, inhibited clonogenic survival and induced cell cycle arrest as well as apoptosis in OAC cells harbouring p53 mutations. Sensitivity to APR-246 correlated with cellular levels of mutant p53 protein. Ectopic expression of mutant p53 sensitised p53-null cells to APR-246, while p53 gene knockdown and knockout diminished drug activity. Importantly, APR-246 synergistically enhanced the inhibitory effects of cisplatin and 5-fluorouracil through p53 accumulation. Finally, APR-246 demonstrated potent antitumour activity in CLX and PDX models, and restored chemosensitivity to a cisplatin/5-fluorouracil-resistant xenograft model. Conclusions: APR-246 has significant antitumour activity in OAC. Given that APR-246 is safe at therapeutic levels our study strongly suggests that APR-246 can be translated into improving the clinical outcomes for OAC patients.