2026· Oncology Research· pp. 1-10· 0 citations· 283 references
TL;DR
This review examines how stemness-associated signaling pathways, including Hedgehog, Notch, and Wnt/ β -catenin, interact with DDR programs to promote CSC survival under genotoxic stress, and summarizes current and emerging therapeutic strategies targeting CSC-specific DDR dependencies.
Abstract
: DNA is continuously challenged by endogenous and exogenous insults, generating lesions that threaten genomic stability. Normal stem cells preserve genome integrity through highly coordinated DNA damage response (DDR) networks involving efficient base excision repair (BER), homologous recombination (HR), cell-cycle checkpoints, and TP53-mediated quality control. Cancer stem cells (CSCs), a rare tumor subpopulation responsible for tumor initiation, metastasis, relapse, and therapeutic resistance, exploit these protective mechanisms while acquiring distinct DNA repair adaptations. This review examines how stemness-associated signaling pathways, including Hedgehog, Notch, and Wnt/ β -catenin, interact with DDR programs to promote CSC survival under genotoxic stress. CSCs frequently exhibit enhanced HR activity driven by RAD51 and BRCA1/2, increased tolerance to replication stress, and sustained DNA repair capacity, contributing to resistance against chemotherapy and radiotherapy. Simultaneously, many CSC populations retain selective deficiencies in non-homologous end joining (NHEJ), nucleotide excision repair (NER), or BER, creating therapeutically exploitable vulnerabilities. We further discuss emerging DDR regulators, including HMCES-mediated protection of abasic sites and polymerase theta (Pol θ )-dependent alternative end joining, as well as the influence of tumor microenvironmental factors such as hypoxia, extracellular vesicles, and cancer-associated fibroblasts on CSC repair capacity and plasticity. We summarize current and emerging therapeutic strategies targeting CSC-specific DDR dependencies, including PARP, ATR, CHK1, and Pol θ inhibitors, replication stress-inducing agents, developmental pathway inhibitors, antibody-drug conjugates carrying topoisomerase I inhibitor payloads, and immunotherapeutic approaches. Particular emphasis is placed on synthetic-lethal strategies and biomarker-guided patient stratification using homologous recombination deficiency signatures, RAD51 foci, and SLFN11 expression. Understanding the unique DDR landscape of CSCs may facilitate the development of rational combination therapies capable of overcoming therapeutic resistance and improving long-term cancer control.
A comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance is provided and emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion are critically discussed.
Hayam Hamdy, Youzhou Li, Chen Li et al.· Molecular Biomedicine· 0 citations
This review summarizes the major DDR pathways, their roles in tumor evolution and immune remodeling, and the rationale and limitations of combining DDR-targeted therapies with immunotherapy and discusses biomarker refinement, resistance mechanisms, and future strategies for translating genomic stress into durable antitumor responses.
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer in adults, and treatment is frequently limited by tumor resistance to temozolomide (TMZ), the standard-of-care chemotherapy. This resistance is often driven by the tumor cell's enhanced capacity to repair TMZ-induced DNA damage. Cell division is normally controlled by two quality-control systems: the spindle assembly checkpoint (SAC), which ensures accurate chromosome segregation during mitosis, and the DNA damage response (DDR), which detects and repairs genomic damage. Growing evidence suggests these two systems are functionally connected, but whether this connection can be exploited pharmacologically in cancer remains unclear. Here, we redesigned a brain-penetrant chemical scaffold to develop G17, a small molecule that selectively inhibits monopolar spindle 1 (Mps1), the central kinase controlling SAC signaling. Characterization of G17 in biochemical and cellular models showed that Mps1 inhibition forces GBM cells to exit mitosis prematurely, resulting in persistent DNA damage and impaired long-term tumor cell growth. Notably, G17 remained active in TMZ-resistant glioblastoma cells that express O6-methylguanine-DNA methyltransferase (MGMT), the enzyme primarily responsible for TMZ resistance, indicating that its activity does not depend on MGMT-mediated DNA repair. Together, these findings provide pharmacological evidence that disrupting SAC signaling can expose a DNA repair vulnerability in glioblastoma and identify Mps1 inhibition as a candidate strategy warranting further investigation in treatment-resistant disease.
Gaurav Rai, S. Kirubakaran· Journal of Biological Chemis...· 0 citations
Key methodological steps for achieving high-efficiency lentiviral transduction and selection are described, enabling the successful application of EPIKOL CRISPR screens in chemoresistant TNBC models.
O. Yedier-Bayram, Elif Ayca Guvener, T. Bagci-Onder· Journal of Visualized Experi...· 0 citations
Replication stress (RS) represents a major vulnerability of cancer cells treated with nucleoside analogs and related antimetabolites; however, tumors frequently acquire tolerance mechanisms that permit survival despite persistent DNA lesions. This review examines molecular determinants of RS tolerance, focusing on human T-cell leukemia virus type 1 (HTLV-1)-mediated adult T-cell leukemia/lymphoma (ATL) as a model of virus-mediated rewiring of DNA damage responses. Chain-terminating nucleoside analogs generate aberrant replication intermediates, including blocked 3’ DNA termini, mis-incorporated bases, and stalled replication forks. In ATL, viral oncoproteins suppress key components of replication stress response pathways, notably tyrosyl-DNA phosphodiesterase 1 (TDP1) and mismatch repair (MMR), thereby creating exploitable repair deficiencies. Consistent with this vulnerability, ATL cells exhibit marked sensitivity to replication stress–inducing agents such as irinotecan (CPT-11) and the chain-terminating nucleoside analog abacavir. Recent CRISPR-based functional genomics studies further identify Schlafen 11 (SLFN11) as an independent and dominant regulator of RS sensitivity. SLFN11 determines the fate of stressed replication forks independently of lesion processing, acting as an execution factor that converts otherwise tolerable RS into irreversible replication arrest. We conclude by discussing therapeutic strategies that exploit RS tolerance defects in ATL, including biomarker-guided nucleoside analog therapy, and rational combination approaches targeting compensatory RS pathways.
Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and tumor recurrence through reversible transitions among stem-like, differentiated, epithelial, and mesenchymal states, which are sustained by interconnected epigenetic mechanisms. To our knowledge, this is the first review to integrate curcumin-mediated regulation of DNA methylation, chromatin remodeling, and non-coding RNAs within a single CSC plasticity framework and to propose the concept of an “epigenetic collapse of CSC plasticity” as a mechanistic explanation for how curcumin may weaken stemness, state switching, and adaptive treatment resistance. Evidence was critically evaluated through structured searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, Google Scholar, and citation tracking, while direct curcumin–epigenetic evidence was distinguished from independent CSC evidence and inferential mechanistic links. Curcumin has been reported to modulate DNMT1 and locus-specific DNA methylation; regulate HDACs, p300/CBP, EZH2, H3K27me3, and BMI1; and alter selected microRNA, long non-coding RNA, and circular RNA pathways, with comparatively stronger evidence involving the miR-34 family, miR-200c, miR-21, H19, and circHN1. However, current evidence is constrained by the predominance of bulk cancer-cell models, heterogeneous formulations and exposure conditions, and the scarcity of epigenetic rescue experiments combined with rigorous functional CSC assays. By unifying previously fragmented epigenetic evidence, this review advances a new evidence-weighted model in which curcumin may suppress CSC persistence not through a single molecular target, but by destabilizing the multilayer epigenetic circuitry that enables plasticity. Curcumin should therefore be regarded as a context-dependent, multilayer epigenetic modulator rather than an established CSC-eradicating therapy, and its translational relevance requires validation in prospectively defined CSC models with pharmacologically justified delivery and exposure conditions.
J. N. Rana, Jayashri Ghosh, Shoail Mumtaz· International Journal of Mol...· 0 citations
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