[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-372801-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-372801-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","alternative-splicing-in-cancer-drug-resistance-mechanisms-and-therapeutic-prospects-review","Alternative splicing in cancer drug resistance - Mechanisms and therapeutic prospects - Review","","Alternative splicing (AS) drives post-transcriptional regulation by enhancing transcriptomic plasticity and expanding proteomic diversity, enabling tumors to adapt under therapeutic pressure. Translation to clinical benefit is limited by the lack of systematic functional annotations for splice variants linked to drug resistance and the scarcity of biomarkers separating de novo from acquired AS-mediated resistance. This review synthesizes current mechanistic insights into AS-driven resistance and evaluates existing strategies addressing these barriers, including therapeutic targeting approaches and integrative modeling opportunities.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/alternative-splicing-in-cancer-drug-resistance-mechanisms-and-therapeutic-prospects-review/372801/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/alternative-splicing-in-cancer-drug-resistance-mechanisms-and-therapeutic-prospects-review/372801.png","ImageObject",300,407,{"name":42,"@type":43},"PakDamar76","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-25","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",9,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What role does alternative splicing play in cancer drug resistance?","Question",{"text":63,"@type":64},"Alternative splicing expands transcriptomic and proteomic diversity, enabling tumors to rewire gene expression and adapt to therapeutic pressure. Aberrant splice variants can support oncogenesis and resistance.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"Why is clinical translation of AS-based findings currently difficult?",{"text":68,"@type":64},"The main obstacles are insufficient systematic functional annotation of resistance-associated splice variants and limited biomarkers that can distinguish de novo from acquired AS-mediated resistance.",{"name":70,"@type":61,"acceptedAnswer":71},"What therapeutic strategies are discussed to overcome splicing-mediated resistance?",{"text":72,"@type":64},"Strategies include spliceosome inhibition (e.g., H3B-8800), and antisense oligonucleotides targeting specific exons or splice junctions (such as targeting exon 2 of MET or other isoforms). The review also notes remaining limitations due to intratumoral heterogeneity and off-target effects.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},372801,1791046827,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":127,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","ONCOLOGY REPORTS 55: 31, 2026  \nAlternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review)  \n* * *  \nWENPU ZHU , ZIKUN WU , CHAI LUV , BANGHE BAO, WEIJIE ZHAO, GUANGLONG CHEN, HANG YANG, HUIHAN AI, FAQIANG LIU and ZHI LI  \nThe Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China  \nReceived July 23, 2025; Accepted November 17, 2025  \nDOI: 10. 3892/or.2025.9036  \nAbstract. Alternative splicing (AS) is one of the principal mechanisms of post‑transcriptional regulation that confers tran‑ scriptomic 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  \nCorrespondence to: Professor Zhi Li, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, Henan 450008, P.R. China  \nE‑mail: [zlyylizhi0316@zzu.edu.cn](zlyylizhi0316@zzu.edu.cn)  \n*Contributed equally  \nAbbreviations: ALL, acute lymphoblastic leukemia; AP, alternative promoter; APA, alternative polyadenylation; AR, androgen receptor; AS, alternative splicing; ASO, antisense oligonucleotide; ATS, alternative trans‑splicing; CML, chronic myeloid leukemia; circRNA, circular RNA; DIs, detained introns; ecircRNA, exonic circRNA; EIciRNA, exon‑intron circRNA; EMT, epithelial‑mesenchymal transition; ER, estrogen receptor; ESE, exonic splicing enhancer; ESS, exonic splicing silencer; ES, exon skipping; HCC, hepatocellular carcinoma; HRR, homologous recombination repair; IR, intron retention; ISE, intronic splicing enhancer; ISS, intronic splicing silencer; LNP, lipid nanoparticle; MDS, myelodysplastic syndromes; MiS, minor spliceosome; MXE, mutually exclusive exons; NMD, nonsense‑mediated decay; NSCLC, non‑small cell lung cancer; PDAC, pancreatic ductaladenocarcinoma; pre‑mRNA, precursor mRNA; scRNA‑seq, single‑cell RNA sequencing; sQTL, splicing quantitative trait loci; SSM, splice‑site mutation; TCGA, The Cancer Genome Atlas; TNBC, triple‑negative breast cancer; UTR, untranslated region  \nKey words: AS, drug resistance, circRNA, spliceosome inhibitor, precision oncology  \ntrans‑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 depen‑ dent 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 inhi‑ bition (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, BRAFand CDYL) . However, therapeutic strategies to target adaptive resistance mechanisms such as AS remain limited, as intratu‑ moral 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","cbCaieZB67ob6SX9","https://ap.wps.com/l/cbCaieZB67ob6SX9","pdf",5700898,"English","# Introduction\n# Molecular architecture of AS in cancer\n# AS-driven drug resistance mechanisms\n# Splicing regulation in cancer immunity, computational discovery and systems crosstalk\n# Therapeutic targeting of aberrant splicing\n# Conclusions and future perspectives","[{\"question\":\"What role does alternative splicing play in cancer drug resistance?\",\"answer\":\"Alternative splicing expands transcriptomic and proteomic diversity, enabling tumors to rewire gene expression and adapt to therapeutic pressure. Aberrant splice variants can support oncogenesis and resistance.\"},{\"question\":\"Why is clinical translation of AS-based findings currently difficult?\",\"answer\":\"The main obstacles are insufficient systematic functional annotation of resistance-associated splice variants and limited biomarkers that can distinguish de novo from acquired AS-mediated resistance.\"},{\"question\":\"What therapeutic strategies are discussed to overcome splicing-mediated resistance?\",\"answer\":\"Strategies include spliceosome inhibition (e.g., H3B-8800), and antisense oligonucleotides targeting specific exons or splice junctions (such as targeting exon 2 of MET or other isoforms). The review also notes remaining limitations due to intratumoral heterogeneity and off-target effects.\"}]","Alternative splicing in cancer drug resistance - Mechanisms and therapeutic prospects - Review | PDF",1790195431,48]