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Singh et al. Cancer Drug Resist. 2025;8:56 Page 7 of 20

of a blood sample, from which plasma or serum is isolated . Biopsy analysis involves detecting epigenetic
[18]
modifications, point mutations, translocations, amplifications, deletions, and assessing protein expression
and phosphorylation [Figure 2] . Functional assays using in vitro or in vivo models are employed to further
[64]
validate the findings. Central to this approach is the detection of circRNAs, which act as stable, non-invasive
biomarkers for tracking therapeutic resistance and guiding personalized cancer treatment decisions . In
[65]
NSCLC, the circRNA hsa_circ_0000190 and hsa_circ_0014235 were found to be upregulated in the plasma
and sponge miRNAs, such as miR-142 and miR-124-3p, which promotes resistance to EGFR tyrosine kinase
inhibitors . In triple-negative breast cancer (TNBC), the circANKS1B found in serum contributed to the
[65]
enhancement of EMT and paclitaxel resistance by targeting miR-148a-3p . Likewise, circ_0005963 in
[66]
plasma from colorectal cancer (CRC) enhances oxaliplatin resistance by governing glycolytic regulation
through the GLUT1/miR-122 axis . CircAKT3 is associated with gastric cancer targets and upregulates the
[67]
autophagy pathway [PI3K/AKT/mechanistic target of rapamycin (mTOR)], helping promote cisplatin
resistance . In HCC, circMTO1 serves as a tumor suppressor but is downregulated in sorafenib
[68]
resistance . GBM-associated circRNAs, including circHIPK3 and circNT5E, have been detected in plasma
[69]
and cerebrospinal fluid (CSF), with alterations in miRNA influencing TMZ resistance . Similarly, circRNAs
[70]
in ovarian (circCELSR1), pancreatic (circ-LDLRAD3), and bladder cancer (circRIP2) regulate pathways
associated with chemotherapy resistance, including the EMT, PI3K/AKT, and transforming growth factor
beta (TGF-β) signaling . Overall, circRNAs from liquid biopsies are a novel source of non-invasive
[71]
biomarkers for monitoring the development of drug resistance in cancer therapies in real time and offer the
opportunity for strategic personalized therapeutic responses and interventions [Table 3] . In the
[6]
investigation of drug resistance, circRNAs have been implicated through several mechanisms. One of the
primary roles of circRNAs is functioning as miRNA sponges - they sequester miRNAs that would otherwise
inhibit oncogenic mRNA targets . For example, circHIPK3 has been shown to sponge miR-124 to confer
[82]
resistance to chemotherapeutic agents in colorectal and bladder cancers . Likewise, in certain cancer
[83]
subtypes, circRNA CDR1as can sequester miR-7, resulting in dysregulated EGFR expression and leading to
resistance to targeted therapies in lung and breast cancers . Beyond intravenously (IV) drug resistance
[84]
mediated through the inhibition of miRNA activity, circRNAs can also affect protein targeting and
transcription regulation, and some may even encode peptides related to multidrug resistance. These
functions further support the role of circRNA as mediators in resistance pathways . The relative ease of
[85]
detecting cirRNAs through liquid biopsies - which provide a minimally invasive method to sample
repeatedly and allow clinicians to track molecular signatures or emerging resistance over the course of
treatment - offers a potential means of evaluating real-time treatment responses . This is particularly
[86]
important in advanced or later-stage cancers, where tumor heterogeneity and limited accessibility make
repeated solid tissue biopsies impractical or impossible for traditional pathological diagnosis . Current
[87]
analyses of circulating circRNA focus on their expression patterns and their utility in inferring the internal
molecular status and characteristics of the primary tumor. At the same time, these circulating circRNAs may
serve as early indicators of emerging therapeutic resistance or treatment failure, enabling timely clinical
intervention guided by rapid circRNA analysis . Liquid biopsy markers offer non-invasive tools for
[88]
monitoring drug resistance in cancer. ctDNA can identify genetic mutations and resistance-related
alterations, but its low abundance in early-stage disease limits its sensitivity . CTCs provide phenotypic and
[89]
genotypic information, yet they are rare and technically challenging to isolate . Exosomes, which carry
[90]
proteins, DNA, and RNA, including circRNAs, offer both molecular stability and functional insights .
[91]
CircRNAs, due to their covalently closed structure, are highly stable and abundant in exosomes, making
them promising biomarkers for real-time tracking of therapeutic resistance across various cancer types
[Table 4] .
[9]

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