Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P