Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies

Esophageal cancer (EC) is a major digestive cancer with a poor 5-year survival rate of less than 20%. EC incidence is projected to increase by 35% in the US by 2025. The two subtypes of EC with distinct histology, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), exhibit deregulation of various oncogenic signaling pathways, distinct pathological features at diagnosis, and distinct mutation profiles. Hence, these cancers require different treatment approaches for their clinical management. ESCC is more prevalent globally, while EAC is prevalent in Western countries, including Europe, North America, and Australia. Notably, two-thirds of US EC cases are EAC. Drug resistance, faster progression, and recurrence are significant problems of EC. Hence, there is a need to identify novel targets in EC progression. Cancer stem cells (CSCs) are a small population of cells in tumors that can self-renew and are responsible for EMT, drug resistance, and recurrence in EC. These serve as attractive targets for drug development and EC treatment. CSCs express surface markers and use the notch, Hedgehog, Hippo, and Wnt-β-catenin pathways to regulate their growth and survival. We are also including a mutation and expression analysis of PANCAN and EC patients for genes/proteins in the notch signaling pathway, using the cBioPortal and TCGA databases. EC was ranked second among cancers with mutations in the notch pathway. Here, we outline the role of notch signaling in EC biology and its inhibitors for EC treatment.