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Page 2 of 20 Singh et al. Cancer Drug Resist. 2025;8:56

circRNAs as circulating biomarkers, emphasizing their potential in precision oncology and future collaborative
translational applications.

INTRODUCTION
The emergence of drug resistance in cancer therapy is one of the greatest obstacles to long-term therapeutic
success. Even with advances in chemotherapy, targeted therapies, and immunotherapies, many solid tumors
relapse in patients due to either intrinsic or acquired resistance mechanisms . While biopsies are considered
[1]
the gold standard for tumor characterization, tissue sampling is invasive, usually performed only once at
diagnosis, and fails to capture the temporal and spatial heterogeneity of tumor biology . As precision
[2]
oncology advances, there is a need for dynamic and non-invasive methods to assess cancer progression and
therapy response . Liquid biopsy presents this opportunity by assessing tumor-derived elements [circulating
[3]
tumor cells (CTCs), circulating tumor DNA (ctDNA), etc.] from biofluids, most commonly blood, urine, or
saliva . New markers in liquid biopsy include circular RNAs (circRNAs) and other non-coding RNAs,
[4]
which have garnered attention as potential biomarkers in the context of drug resistance due to their
structural stability, abundance, linearity of representation, and biologically relevant functional states .
[5]
CircRNAs represent a class of endogenous non-coding RNAs identified by a covalently closed-loop structure
that is resistant to degradation by exonucleases . Their circular structure confers exceptional stability in
[6]
bodily fluids, making them promising candidates for biomarker discovery . CircRNAs were initially
[7]
dismissed as transcriptional noise, but they are now recognized as regulators of biological processes such as
proliferation, apoptosis, autophagy, and gene expression . A growing body of evidence has shown that
[8]
circRNAs are involved in the development of resistance to anticancer therapies through multiple
mechanisms, including sponging microRNAs (miRNAs), interacting with RNA-binding proteins (RBP),
regulating signal transduction pathways, and modulating transcription .
[9]

The finding of circulating circRNAs through liquid biopsy represents a new frontier for non-invasive
monitoring of drug resistance in a cancer context . Given that circRNAs are stable in plasma and other
[10]
fluids, we can readily quantify circRNA presence and abundance through innovative molecular techniques,
including quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA sequencing
(RNA-seq), and droplet digital PCR (ddPCR) . Therefore, researchers have been able to link resistance to
[5]
specific therapies with cancer-specific circRNA signatures . For example, in non-small cell lung cancer
[11]
(NSCLC), circRNA_102231 was shown to be overexpressed in cases where NSCLC patients had resistance to
gefitinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) . The mechanism
[12]
involved acting as a sponge to miR-130a-3p, which resulted in upregulation of oncogenic miR targets. As
another example, in the context of breast cancer, circRNA cerebellar degeneration-related protein 1 gene
(CDR1) antisense RNA (CDR1as) was correlated with tamoxifen resistance through modulation of the
miR-7/EGFR pathway . Cancer drug resistance is often multifaceted and involves changes in drug
[13]
metabolism, expression of efflux pumps, DNA repair, epithelial-mesenchymal transition (EMT), and
stemness. CircRNAs have the potential to disrupt many of these pathways . For example, circHIPK3 has
[14]
been shown to support chemoresistance by targeting various downstream processes in colorectal and bladder
cancers . The involvement of circRNAs in modulating resistance at multiple levels highlights their promise
[15]
as unifying biomarkers that profile the changing resistance landscape during treatment . In addition, it is
[16]
plausible that circRNAs may provide a better biological picture of tumor heterogeneity than a biopsy from
only one tumor site, given that circRNAs may be from diverse tumor sites . Despite the very optimistic
[17]
possibilities, challenges remain in circulating circRNAs for clinical purposes . First, protocols for sample
[18]
collection, RNA isolation, and data normalization must be established to ascertain reproducibility. Second,
there may be detection and validation issues with lowly abundant circRNAs ; circumvention of low
[19]
amounts of rare circRNAs may require a very sensitive detection method . A third significant challenge is
[20]

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