Preclinical assessment of AZD1775 and Cisplatin in the treatment of esophageal adenocarcinoma
Esophageal adenocarcinoma (EAC), a subtype of esophageal cancer associated with obesity and gastric reflux, has seen a dramatic rise in incidence in the United States and western Europe. The standard of care for EAC has relied upon a multidrug chemotherapy combined with radiation, which carries significant toxic side effects. Despite this aggressive treatment, the five-year survival rate for EAC has remained at 18%, demonstrating a need for more efficient and less toxic treatments for EAC. Recent genomic analyses of EAC show that the majority of EAC tumors harbor mutations in TP53, a gene coding for tumor suppressor p53. Mechanistically, p53 functions to regulate the cell cycle, specifically the G1/S checkpoint, where errors in DNA replication are repaired. The loss of p53 function leads to reliance on the G2/M checkpoint for DNA repair. Inhibition of the G2/M checkpoint in p53 mutant cancer cells causes increased DNA damage and subsequently cell death. This vulnerability of tumors has potential for clinical application, leading to the development of drugs that inhibit proteins responsible for the G2/M checkpoint. Based upon the reported incidence of p53 inactivation in EAC, we investigated whether AZD1775, a small molecule inhibitor of G2/M checkpoint regulator Wee1, could have value in treating EAC. AZD1775 treatment both in vivo and in vitro suggested that the combination of AZD1775 and cisplatin, a DNA damaging agent, had effects equivalent to the current standard of care, supporting the use of AZD1775 as a less toxic alternative therapy. In investigating the mechanisms for AZD1775 cytotoxicity in EAC, expression of the tumor suppressor p21, thought to be a transcriptional target of p53, was highly expressed in p53-mutant EAC cell lines and correlated with reduced sensitivity to AZD1775/Cisplatin treatment. Depletion of p21, using shRNA, resulted in increased cytotoxicity upon treatment with AZD1775 compared to the vector control. Further experiments will investigate the potential of p21 as a possible biomarker indicative of sensitivity to AZD17.