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APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma
  1. David S H Liu1,2,
  2. Matthew Read1,2,
  3. Carleen Cullinane2,3,
  4. Walid J Azar4,
  5. Christina M Fennell1,
  6. Karen G Montgomery1,
  7. Sue Haupt5,
  8. Ygal Haupt5,
  9. Klas G Wiman6,
  10. Cuong P Duong7,
  11. Nicholas J Clemons1,2,
  12. Wayne A Phillips1,2,7,8
  1. 1Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  3. 3Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. 4Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. 5Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. 6Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden
  7. 7Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  8. 8University of Melbourne Department of Surgery, St. Vincent's Hospital, Melbourne, Victoria, Australia
  1. Correspondence to Dr Wayne A Phillips, Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1 A'Beckett Street, Melbourne, VIC 8006, Australia; wayne.phillips{at}petermac.org

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.

  • OESOPHAGEAL CANCER
  • ONCOGENES
  • DRUG DEVELOPMENT

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