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Review Open Access

Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)

  • Authors:
    • Wenpu Zhu
    • Zikun Wu
    • Chai Luv
    • Banghe Bao
    • Weijie Zhao
    • Guanglong Chen
    • Hang Yang
    • Huihan Ai
    • Faqiang Liu
    • Zhi Li
  • View Affiliations / Copyright

    Affiliations: The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 31
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    Published online on: December 5, 2025
       https://doi.org/10.3892/or.2025.9036
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Abstract

Alternative splicing (AS) is one of the principal mechanisms of post‑transcriptional regulation that confers transcriptomic plasticity and proteomic diversity in cancer, thereby enabling tumor adaptation to therapeutic pressure. However, two obstacles impede the translation of these findings into clinical benefit: The absence of systematic functional annotation of the numerous splice variants associated with drug resistance and the paucity of biomarkers capable of distinguishing de novo from acquired splice‑mediated resistance. In the present review, the current mechanistic understanding of AS‑driven drug resistance was briefly synthesized, and it was evaluated how existing strategies address these challenges. It was also described how knowledge of dysregulated splicing networks, due to mutations in cis‑regulatory elements such as ESS, overexpression of trans‑acting factors such as SRSF1, as well as mechanisms such as alternative trans‑splicing, in which the spliceosome interacts with splice sites on two distinct RNA molecules and which can be driven by complementary sequences or other trans‑acting factors, could be used to more accurately identify tumors dependent on aberrant splicing for survival. In addition, it was outlined how targeting aberrant splice variants to overcome therapeutic resistance can be achieved, such as through spliceosome inhibition (for example, H3B‑8800) or antisense oligonucleotides directed to a specific exon or splice junction (for example, targeting exon 2 of MET, which is implicated in cis‑regulated AS isoforms, or alternatively spliced isoforms of BCL2L1, BRAF and CDYL). However, therapeutic strategies to target adaptive resistance mechanisms such as AS remain limited, as intratumoral heterogeneity may facilitate the emergence of resistant subpopulations, and as most spliceosome inhibitors are not spliceosome‑specific, they exhibit off‑target effects. Importantly, it was also discussed how pan‑cancer splicing databases and single‑cell isoform expression profiling can be integrated with deep‑learning models, thereby informing the design of therapeutic strategies to overcome splicing‑mediated adaptive drug resistance. Notably, such integration will enable the rational design of isoform‑specific combination regimens to dismantle drug‑resistance circuits. It is anticipated that the present review will assist the scientific community, including both basic and translational researchers, in translating these findings into interventions that mitigate therapeutic failure in recalcitrant cancers.
View Figures

Figure 1

Splicing resistance map: Canonical
classification of alternative splicing events. A schematic overview
of the seven canonical types of AS events that constitute the
foundational elements of the oncogenic ‘splicing resistance map’:
Exon skipping also called cassette exon, intron retention,
alternative promoter, alternative polyadenylation, alternative 3’
splice site, alternative 5’ splice site (5’ SS) and mutually
exclusive exons. This map depicts the repertoire of evolutionarily
conserved AS mechanisms that are hijacked in cancer to enhance
tumor survival, proliferation, and resistance to therapy. The
pan-cancer prevalence of each event type is quantitatively
summarized in Fig. S1. AS,
alternative splicing.

Figure 2

Alternative splicing mechanism and
spliceosome complex proteins with their functions. Pre-mRNA
splicing is the process of removal of intronic regions and joining
the exons to form mature mRNA. Trans-acting factors consist of
splicing factors which recognize conserved premRNA sequences
(cis-regulatory elements) and recruit the core spliceosome
machinery which coordinates and executes the excision of introns.
U2 snRNP (for example, SF3B1) recognizes and binds to branch point
A, initiating spliceosome assembly and splicing reactions; SR
proteins (for example, SRSF1) primarily bind to ESE elements (with
partial assistance from ISE elements) to promote splicing; hnRNPs
(for example, hnRNP A1) inhibit splicing by binding to ESS/ISS
elements; epigenetic regulation (for example, m6A modification)
acts on exons through recruiting reader proteins (for example,
YTHDC1). These factors collectively act on pre-mRNA, regulating
alternative splicing and ultimately generating distinct mRNA
transcripts. ESE, exonic splicing enhancer; ISE, intronic splicing
enhancer; ESS, exonic splicing silencer; ISS, intronic splicing
silencer.

Figure 3

Canonical vs. non-canonical splicing
events and their associated resistance mechanisms. (A) The AS can
be classified into two categories, canonical splicing events: ACS
and non-canonical splicing events: ATS and ABS. There are seven
subtypes of ACS, consistent with the content in Fig. 1. ABS is a non-canonical RNA
processing mechanism distinct from linear splicing, wherein a
downstream splice donor site covalently joins an upstream splice
acceptor site, forming a closed-loop RNA structure called circular
RNA (circRNA). ATS connects fragments from two distinct primary RNA
transcripts generating chimeric RNAs. ATS can be classified into
two types based on the origin of the primary RNA transcripts,
involving intragenic and intergenic trans-splicing. (B) Specific
examples of drug resistance mechanisms due to cis-splicing. Exon
skipping (left panel) confers resistance through alterations in
protein structure and function. Examples include: deletion of the
SH3 domain in BCR-ABL1, which reduces asciminib binding in chronic
myeloid leukemia (CML); skipping of exon 11 in BRCA1, which
restores homologous recombination repair (HRR) and leads to PARP
inhibitor (PARPi) resistance; and inclusion of exon 6a in NT5C2,
which promotes dimerization and enhances enzymatic activity in
acute lymphoblastic leukemia (ALL). Intron retention (right panel)
facilitates resistance via rapid stress response and regulation of
gene expression. Key instances are: temozolomide-induced detained
introns in MLH1, resulting in mismatch repair (MMR) deficiency in
glioblastoma; radiation-induced intron retention in GPX1, mediated
by NONO, that impairs its antioxidant function, elevates reactive
oxygen species (ROS), and promotes radiation resistance in
glioblastoma; SRSF5-mediated retention of intron 9 in PKM,
upregulating PKM2 to enhance glycolysis and confer oxidative stress
resistance in colorectal cancer; widespread intron retention
following RBM39 loss, which triggers nonsense-mediated decay (NMD)
of oncogenic transcripts in acute myeloid leukemia (AML); and
finally, intron retention in LZTR1 in myelodysplastic syndromes
(MDS) that evades NMD, thereby activating the RAS pathway and
driving leukemogenesis. (C) Specific examples of drug resistance
mechanisms due to back-splicing. The miRNA sponge mechanism (left
panel) is illustrated by the following: exosomal circFARP1 derived
from cancer-associated fibroblasts sequesters miR-660-3p, leading
to upregulation of LIF and activation of STAT3 signaling, thereby
promoting stemness and gemcitabine resistance in pancreatic ductal
adenocarcinoma; circPARD3 acts as a sponge for miR-145-5p,
activating the PRKCI/AKT/mTOR pathway to suppress autophagy and
induce cisplatin resistance in laryngeal squamous cell carcinoma;
and circCDYL2 sequesters miR-199a-5p, resulting in elevated GRB7
expression and subsequent FAK signaling activation, which
contributes to trastuzumab resistance in HER2-positive breast
cancer. Protein-protein interactions (right panels) are
demonstrated through two examples: circCDYL2 directly binds to and
stabilizes GRB7, sustaining HER2/AKT/ERK signaling; and
circRNA-CREIT scaffolds the HACE1-mediated degradation of PKR,
which disrupts stress granule formation and promotes doxorubicin
resistance in triple-negative breast cancer. (D) Specific examples
of drug resistance mechanisms due to trans-splicing. In
glioblastoma, Rbfox2 stabilized by FBXO7 promotes trans-splicing,
generating FoxM1 variants that upregulate stemness markers (for
example, CD44, ID1) and confer chemoresistance. In prostate cancer,
FOXA1 facilitates the inclusion of FLNA exon 30 via trans-splicing,
resulting in cytoskeletal remodeling and resistance to androgen
receptor inhibitors. Trans-splicing between sense and antisense
transcripts also produces cross-strand chimeric RNAs (such as
cscR-8-21 and cscR-2-22), which contribute to cancer cell survival
and have been implicated in therapy resistance. Furthermore, in
chronic myeloid leukemia, trans-splicing gives rise to truncated
BCR-ABL1 isoforms (for example, b3a3) that lack the SH3 domain,
leading to constitutive kinase activity and resistance to
allosteric inhibitors such as asciminib. ACS, alternative
cis-Splicing; ATS, alternative trans-splicing; ABS, alternative
back-splicing

Figure 4

Multimodal strategies to overcome
cancer drug resistance. When combined with standard chemotherapy or
radiotherapy, appropriately dosed splicing modulators, antisense
oligonucleotides, and circRNA-directed nanotherapeutics produce
synergistic antitumor responses. This approach counteracts drug
resistance by correcting aberrant splicing and concurrently reduces
off-target toxicity in healthy tissues, leading to a significantly
widened therapeutic index.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu W, Wu Z, Luv C, Bao B, Zhao W, Chen G, Yang H, Ai H, Liu F, Li Z, Li Z, et al: Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review). Oncol Rep 55: 31, 2026.
APA
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G. ... Li, Z. (2026). Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review). Oncology Reports, 55, 31. https://doi.org/10.3892/or.2025.9036
MLA
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G., Yang, H., Ai, H., Liu, F., Li, Z."Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)". Oncology Reports 55.2 (2026): 31.
Chicago
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G., Yang, H., Ai, H., Liu, F., Li, Z."Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)". Oncology Reports 55, no. 2 (2026): 31. https://doi.org/10.3892/or.2025.9036
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu W, Wu Z, Luv C, Bao B, Zhao W, Chen G, Yang H, Ai H, Liu F, Li Z, Li Z, et al: Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review). Oncol Rep 55: 31, 2026.
APA
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G. ... Li, Z. (2026). Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review). Oncology Reports, 55, 31. https://doi.org/10.3892/or.2025.9036
MLA
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G., Yang, H., Ai, H., Liu, F., Li, Z."Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)". Oncology Reports 55.2 (2026): 31.
Chicago
Zhu, W., Wu, Z., Luv, C., Bao, B., Zhao, W., Chen, G., Yang, H., Ai, H., Liu, F., Li, Z."Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)". Oncology Reports 55, no. 2 (2026): 31. https://doi.org/10.3892/or.2025.9036
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