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DDX11 as a potential therapeutic target in esophageal squamous cell carcinoma
Thesis

DDX11 as a potential therapeutic target in esophageal squamous cell carcinoma

Jeel Shah
Master of Science (M.S.), Drexel University
Jul 2026
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Shah_Jeel_20266.32 MB
PDF Embargoed Access, Embargo ends: 31 Aug 2028

Abstract

Esophageal squamous cell carcinoma (ESCC) is characterized by uncontrolled cell growth, elevated replication stress, genomic instability, and accumulation of DNA damage, yet effective therapeutic options remain limited. To sustain rapid growth under these conditions, cancer cells rely on replication stress response and DNA repair pathways that preserve genomic integrity. DDX11 is a DNA helicase that is upregulated in multiple cancer types, including ESCC and related head and neck squamous cell carcinoma. DDX11 interacts with Timeless, a component of the fork-protection complex, and resolves replication barriers such as G-quadruplexes (G4s), suggesting its role in maintaining fork integrity and genomic stability. Despite these established functions, the role of DDX11 in ESCC remains unknown. Here, we investigated the consequences of DDX11 depletion and evaluated its potential as a therapeutic target. We found that DDX11 loss increased replication stress and DNA damage, as demonstrated by elevated phosphorylation of the replication checkpoint kinases Chk1 and RPA32, and increased expression of the compensatory helicase FANCJ. DDX11 depletion also led to activation of the cGAS-STING innate immune signaling pathway, with alteration in the expression of downstream inflammatory cytokines. Furthermore, loss of DDX11 also sensitized cancer cells to G4 stabilizers and PARP inhibitors. Together, these findings demonstrate that DDX11 is required for maintaining fork integrity and renders ESCC cells more susceptible to targeted therapies, supporting DDX11 as a promising therapeutic target.

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