Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma

BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adeno-carcinoma (EAC) and other solid tumors. METHODS: An in-tegrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple ap-proaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridi-zation. RESULTS: Expression of 4 deoxyribonucleases corre-lated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhi-bition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 over -expression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evalu-ation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregu-lates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

Automated summary

This study identified APE1 as a driver of genomic evolution in esophageal adeno-carcinoma and other solid tumors. APE1 suppression caused cell cycle arrest, impaired growth, and increased cell toxicity, while APE1 overexpression led to massive chromosomal instability and oncogenic transformation. Inhibitors targeting APE1 have the potential to treat EAC and other cancers by regulating genomic instability.