Evidence map›Paper›PMID 41591631›Full record

ArticleGenes & genomics2026

Epitranscriptomic regulation of NVP-BEZ235 resistance in ccRCC via the YTHDF3-SYNM regulatory pathway.

Ruiang Wang, Cheng Lu, Erchang Shen, Xi Zhang, Xinchi Xu, Xiaoyang Cao, Tian Rao, Xiaohan Ren, Yiyang Liu, Chen Xu and 1 more

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Article in Genes & genomics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Beyond mBiomedicines · 2026
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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Ruiang Wang *The First Clinical Medical College, Faculty of Medicine, Yangzhou University, Yangzhou, 225001, China.
Cheng Lu *Department of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, China.
Erchang Shen *Nanjing Medical University, Nanjing, 210029, China.
Xi Zhang *Department of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Xinchi XuDepartment of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Xiaoyang CaoDepartment of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Tian RaoDepartment of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Xiaohan RenDepartment of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Yiyang LiuDepartment of Urology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China. liu820700@163.com.
Chen XuDepartment of Urology, Suzhou Ninth People's Hospital affiliated to Soochow University, Suzhou, 215000, China. chenadoc@126.com.
Xiaoxiang WangDepartment of Urology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, China. 18936489811@163.com.

Funding

the Youth Project of "Gusu healthy" GSWS2022110
6 · The paper itself

Abstract

backgroundNVP-BEZ235 is a dual PI3K/mTOR inhibitor with promising antitumor activity in clear cell renal cell carcinoma (ccRCC). However, the mechanisms underlying acquired drug resistance remain incompletely defined.

objectiveTo investigate whether epitranscriptomic regulation-specifically N6-methyladenosine (m6A) modification and its reader YTHDF3-drives reversible, non-genetic resistance to NVP-BEZ235 in ccRCC, and to identify key downstream effector genes.

methodsNVP-BEZ235-resistant models were established from 786-O and PTEN-deficient Caki-1ko ccRCC cells via chronic drug exposure. Drug withdrawal assays were performed to evaluate the reversibility of resistance. Expression of m6A regulators was assessed by qRT-PCR and Western blotting. YTHDF3 was silenced using lentiviral shRNA, and changes in NVP-BEZ235 sensitivity were evaluated by CCK-8 and cell-cycle assays. Genome-wide m6A-RIP-seq and RNA-seq were integrated to define transcripts with coordinated changes in m6A methylation and expression, and core causal genes for ccRCC were prioritized by summary-based Mendelian randomization (SMR). YTHDF3-RNA interactions and dynamic m6A changes were validated by RIP-qPCR and MeRIP-qPCR, and the functional role of SYNM was tested by loss-of-function studies.

resultsNVP-BEZ235-resistant cells displayed a reversible, nonheritable phenotype, partially regaining drug sensitivity after short-term drug withdrawal. YTHDF3 was selectively upregulated in resistant cells, and its knockdown significantly lowered the IC50 of NVP-BEZ235 and suppressed proliferation. Integrated m6A-RIP-seq/RNA-seq analyses revealed extensive reprogramming of m6A methylation, and SMR identified SYNM as a core m6A-regulated gene associated with increased ccRCC risk. SYNM was overexpressed in ccRCC tissues and positively correlated with YTHDF3 expression. YTHDF3 bound SYNM mRNA in resistant cells, while m6A levels and expression of both YTHDF3 and SYNM were dynamically reversible upon drug withdrawal. Silencing SYNM robustly resensitized resistant cells to NVP-BEZ235.

conclusionsReversible resistance to NVP-BEZ235 in ccRCC is driven, at least in part, by an m6A-dependent YTHDF3-SYNM axis. Targeting YTHDF3 or SYNM may provide a rational strategy to overcome PI3K/mTOR inhibitor resistance in ccRCC.

Indexed as

Carcinoma, Renal CellDrug Resistance, NeoplasmImidazolesKidney NeoplasmsQuinolinesRNA-Binding ProteinsAdenosineCell Line, TumorEpitranscriptomeGene Expression Regulation, NeoplasticHumansRNA MethylationAdenosinedactolisibImidazolesN-methyladenosineQuinolinesRNA-Binding ProteinsYTHDF3 protein, humanClear cell renal cell carcinomaDrug resistancem6ANVP-BEZ235SYNMYTHDF3

Identifiers

PMID41591631

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.