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Utilizing the DNA Damage Response Mechanism for Cancer Treatments

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Dr. Daniel Chi-Wei Chen

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Guest Editor

Department of Biology, College of Arts and Sciences, Appalachian State University, Boone, NC 28608, USA
Interests: DNA damage response; cancer metabolism; replication stress; therapeutic resistance; combination therapy

Special Issue Information

Dear Colleagues,

The DNA damage response (DDR) is a fundamental cellular network that preserves genome integrity under endogenous and exogenous stress. In cancer, DDR pathways are frequently dysregulated. It enables tumor cells to tolerate genomic instability, adapt to metabolic and microenvironmental stress, and develop resistance to chemotherapy, radiotherapy, and targeted agents. At the same time, these alterations create exploitable vulnerabilities that can be leveraged for therapeutic benefit.

Recent discoveries have expanded the DDR framework beyond classical DNA repair to include emerging genes and non-canonical pathways involved in chromatin remodeling, RNA processing, metabolic adaptation, immune signaling, and replication stress tolerance. Herein, the DDR-targeted agents represent new therapeutic opportunities and are advancing toward clinical application through synthetic lethality-based approaches and rational combination strategies.

This Special Issue, Utilizing the DNA Damage Response Mechanism for Cancer Treatments, aims to highlight emerging DDR genes, pathways, and therapeutic strategies. This Special Issue seeks original research articles; reviews; and perspectives on molecular, translational, and preclinical or clinical studies. This Special Issue aims to advance DDR-based therapies and deepen our understanding of targeting this complex pathway in human tumors.

Dr. Daniel Chi-Wei Chen
Guest Editor

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21 pages, 1134 KB

Open AccessArticle

The Association of Social and Biological Factors with Clinical Outcomes in Patients with Lung Cancer and DNA Damage Repair Pathway Mutations: A Single-Institution Experience

by Ahmad Nanaa, Jeremy Kao, Martin Davis, Mary Pasquinelli, Margaret Wright Geise, Li Liu, Ryan Huu-Tuan Nguyen and Frank Weinberg

Cancers 2026, 18(16), 2606; https://doi.org/10.3390/cancers18162606 - 13 Aug 2026

Viewed by 288

Abstract

Background: Lung cancer remains the leading cause of cancer-related mortality in the United States, characterized by poor overall survival rates (OS), particularly for advanced-stage disease. While smoking is a primary risk factor, other contributors include environmental exposures, genetics, comorbidities, and socioeconomic factors. Methods: We included 232 patients with lung cancer (96% NSCLC). Patients were categorized into DNA damage response (DDR)-mutant (DDR^mt, n = 67, 29%) and DDR-wild-type (DDR^wt, n = 165, 71%) groups. We evaluated the correlations between individual and socioeconomic factors between DDR^mt and DDR^wt lung cancer patients. Results:Nineteen DDR genes were identified, with ARID1A(31.3%), CHEK2 (19.4%), ATM (14.9%), BRCA2 (14.9%), ATRX (11.9%), MUTYH (11.9%), ATR (8.9%), and MSH6 (5.9%) being the most common. The DDR^mt group had a significantly higher median tumor mutational burden (TMB) (12 vs. 9; p = 0.006) and a higher prevalence of adenocarcinoma (85.1% vs. 64.8%, p = 0.003). Logistic regression identified adenocarcinoma histology (OR = 10.03, p = 0.002) and lower area deprivation index (OR = 0.98, p = 0.04) as predictors of DDR mutation status. Having advanced stage at diagnosis was associated with, age (p = 0.03), lack of lung cancer screening (p < 0.001), and adenocarcinoma histology (p < 0.001). While median OS was 61 months for the DDR^mt group vs. 44 months for the DDR^wt group (p = 0.654), patients with ATR mutations had significantly shorter survival (13 vs. 67 months; p = 0.0008). Population-level factors, including food insecurity (HR = 2.33, p = 0.002), lack of insurance (HR = 2.39, p = 0.008), and proximity to potential chemical accidents (HR = 1.73, p = 0.037), were significant predictors of OS. Conclusions: These findings suggest that DDR^mt lung cancers represent a biologically distinct subgroup characterized by higher tumor mutational burden and enrichment for adenocarcinoma histology; however, DDR mutation status alone was not associated with overall survival. Instead, outcomes appeared to vary by individual DDR gene, with ATR alterations identifying a subgroup with particularly poor survival. In parallel, food insecurity, lack of insurance, and proximity to potential environmental hazards were associated with outcomes, highlighting the need to integrate genomic biomarkers with social and environmental determinants of health. These data suggest the need for future prospective studies incorporating treatment-response data, longitudinal social determinants of health (SDOH) assessment, and environmental exposure measures to define how DDR alterations can guide precision oncology strategies while addressing modifiable barriers to equitable cancer care. Full article

(This article belongs to the Special Issue Utilizing the DNA Damage Response Mechanism for Cancer Treatments)

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20 pages, 3611 KB

Open AccessArticle

Rac1 GTPase Regulates the SCF^βTrCP-Mediated Degradation of Claspin and the Cellular Response of Pancreatic Cancer Cells to Gamma Rays

by Neha Chaudhary, Tabbatha N. Somers, Surinder K. Batra, Ying Yan and Michel M. Ouellette

Cancers 2026, 18(12), 1908; https://doi.org/10.3390/cancers18121908 - 11 Jun 2026

Viewed by 408

Abstract

Background/Objectives: Pancreatic ductal adenocarcinomas (PDACs) are lethal tumors exhibiting resistance to most cancer therapeutics, particularly DNA-damaging agents. The KRAS oncogene drives PDACs, and many of these tumors are addicted to it and its downstream effectors. One such effector is Rac1, a small GTPase involved in actin cytoskeleton remodeling and regulation of the DNA damage response. We previously showed that Rac1 inhibition blocks activation of ATM/Chk2 and ATR/Chk1 pathways in response to gamma rays, sensitizing PDAC cells to radiation. Methods: Western blot analyses were used to assess the impacts of Rac1 inhibition on the components of the ATR/Chk1 cascade. Results: Here, we show that Rac1 inhibition disrupts ATR/Chk1 signaling by promoting degradation of Claspin, a key component of the fork protection complex needed for the Ser345-phosphorylation of Chk1 by ATR. In PDACs and normal pancreatic ductal cells, Rac1 inhibition (via inhibitors or siRNA) decreased Claspin protein levels without affecting its mRNA, reflecting a >3-fold reduction in Claspin’s half-life. Claspin contains a phosphodegron recognized by SCF^βTrCP E3 ubiquitin ligase when phosphorylated at Ser30/Ser34, a process involving PLK1 kinase. In PDAC cells, Claspin degradation upon Rac1 inhibition required the proteasome and βTrCP1/2 proteins, and was blocked by the mutagenesis of Ser30/Ser34, but occurred independently of PLK1 activity. Although Rac1 inhibitors reduced Claspin in both normal and cancer cells, PDAC cells may be uniquely vulnerable due to elevated replication stress and greater reliance on ATR/Chk1. Accordingly, Claspin depletion sensitized PDAC cells but not normal cells to gamma rays, inducing apoptosis only in cancer cells. Conclusions: These findings identify Rac1 as a critical regulator of ATR/Chk1 signaling through stabilization of the fork protection protein Claspin. Rac1 inhibition promotes the βTrCP-dependent, proteasome-mediated degradation of Claspin via its phosphodegron, thereby impairing Chk1 activation in response to DNA damage. Full article

(This article belongs to the Special Issue Utilizing the DNA Damage Response Mechanism for Cancer Treatments)

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