ORCID

0009-0009-0489-8245 (Brown)

Document Type

Article

Publication Date

2025

DOI

10.3390/cancers17122050

Publication Title

Cancers

Volume

17

Issue

12

Pages

2050 (31 pp.)

Abstract

Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage.

Rights

© 2025 by the authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Original Publication Citation

Moore, L. L., Jaboin, J., Brown, M. L., & Houchen, C. W. (2025). Balancing regeneration and resistance: Targeting DCLK1 to mitigate gastrointestinal radiation injury and oncogenesis. Cancers, 17(12), Article 2050. https://doi.org/10.3390/cancers17122050

Download

Share

COinS