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Singh et al. Cancer Drug Resist. 2025;8:56 Page 5 of 20

Table 1. Key circRNAs implicated in cancer drug resistance: pathways, mechanisms, and clinical applications
Target Mechanism of drug Clinical relevance/potential
S.N. CircRNA name Tumor type Ref.
pathway/gene resistance use
Acts as a sponge to suppress
Colorectal, tumor-suppressor miRNAs; Biomarker for chemotherapy
1 circHIPK3 miR-124, miR-558 [33]
lung, bladder promotes resistance to 5-FU and resistance
cisplatin
Interferes with cell cycle
Breast, lung, Prognostic marker; potential
2 circFOXO3 FOXO3, p21, CDK2 regulation and apoptosis [38]
gastric therapeutic target
pathways
Oral
3 circRNA_100290 squamous cell miR-29 family Modulates cell proliferation and Diagnostic and drug response [39]
carcinoma cisplatin resistance predictor
Promotes gefitinib resistance by
4 circ_0001946 NSCLC miR-135a-5p, STAT6 activating STAT6/PI3K/AKT Potential marker for EGFR-TKI [40]
pathway resistance monitoring
Regulates drug response via
5 circRNA CDR1as Glioma, breast miR-7, EGFR pathway miRNA sponging and EGFR Associated with resistance to [41]
signaling targeted therapy
Facilitates paclitaxel resistance by Marker of chemoresistance and
6 circ-PVT1 Gastric cancer miR-124-3p, ZEB1 [36]
modulating EMT poor prognosis
Enhances doxorubicin sensitivity
7 circMTO1 HCC miR-9/p21 Therapeutic sensitization target [42]
via tumor suppressor pathways
Promotes TMZ resistance via Candidate for targeting glioma
8 circAKT3 GBM PI3K/AKT pathway [43]
maintaining stemness stem cells
Enhances resistance by
Breast, lung Liquid biopsy candidate for
9 circ-ABCB10 miR-1271, BCL2 modulating apoptosis and cell [29]
cancer resistance monitoring
survival
circRNAs: Circular RNAs; miRNAs: microRNAs; 5-FU: 5-fluorouracil; FOXO3: forkhead box O3; CDK2: cyclin-dependent kinase 2; NSCLC: non-small
cell lung cancer; STAT6: signal transducer and activator of transcription 6; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; EGFR-TKI:
epidermal growth factor receptor-tyrosine kinase inhibitor; ZEB1: zinc finger E-box-binding homeobox 1; EMT: epithelial-mesenchymal transition;
HCC: hepatocellular carcinoma; GBM: glioblastoma; TMZ: temozolomide; BCL2: B-cell lymphoma 2.

can obtain biospecimens from patients who might otherwise be ineligible due to poor general condition,
prior trauma, or advanced disease . Fourth, circulating circRNAs can originate from multiple tumor sites,
[59]
offering a more comprehensive view of the disease and potentially revealing emerging resistance profiles
simultaneously [59,60] . Recent advancements in technology have enabled sensitive and specific detection of
circRNAs from plasma and serum samples using qRT-PCR, ddPCR and RNA-seq methods . These
[60]
platforms allow for profiling circRNA expression changes during treatment, which may provide early signals
of therapeutic failure or developing resistance. Numerous preclinical and clinical studies have identified
circRNA signatures correlated with chemoresistance, resistance to tyrosine kinase inhibitors, and resistance
to immune checkpoint blockade, highlighting their translational potential . Despite these promising
[61]
advancements, challenges exist. There remains a lack of standardization for the many pre-analysis variables
that can influence circRNA measurements (e.g., sample processing in clinical laboratories, RNA isolation
protocols, and data normalization) . Additionally, further validation through large, multi-center clinical
[62]
studies is required to assess the diagnostic or prognostic value of specific circRNAs. Combining circRNA
biomarkers with other molecular and clinical measures may enhance their predictive power and increase
their utility in personalized medicine . In summary, the liquid biopsy-based detection of circulating
[63]
circRNAs provides a new, effective paradigm for non-invasive tracking of drug resistance in cancer . As
[6]
research continues and the technology advances, it is possible that circRNA profiling will become a relevant
component of the clinical oncology arsenal, enabling real-time treatment guidance for drug resistance and
improving outcomes in the era of precision oncology .
[44]

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