Evidence map›Paper›PMID 42886303›Full record

ArticleMolecular biology reports2026

NEK2 promotes trastuzumab resistance in gastric cancer through WTAP/YTHDF1-dependent m6A regulation of FN1.

Zengchao Shen, Jingjing Zheng, Yongtao Chen, Junwei Liu, Minyue Li, Hua Shi

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Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

6 authors.

Zengchao ShenDepartment of Gastroenterology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Jingjing ZhengGastrointestinal Surgery, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China.
Yongtao ChenDepartment of Gastroenterology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Junwei LiuDepartment of Gastroenterology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Minyue LiDepartment of Gastroenterology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.
Hua ShiDepartment of Gastroenterology, Lishui Municipal Central Hospital, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China. schwa204@sohu.com.

Funding

The Science and Technology Program of Lishui: Lishui Public Welfare Technology Application Research Plan Project 2023GYX68The Science and Technology Program of Lishui: Lishui Public Welfare Technology Application Research Plan Project 2024GYX33Zhejiang Medicine and Health Technology Plan 2024KY1844
6 · The paper itself

Abstract

backgroundTrastuzumab resistance remains a major challenge in the clinical management of gastric cancer (GC), and effective strategies to overcome resistance are still limited. NEK2 has been implicated in GC progression and therapeutic resistance in several tumor types; however, its role in trastuzumab resistance in GC and the underlying mechanisms remain unclear. METHODS AND

resultsTrastuzumab-resistant NCI-N87/TR cells were established from parental NCI-N87 cells by stepwise exposure to increasing concentrations of trastuzumab. NEK2 was markedly upregulated in trastuzumab-resistant GC cells. Silencing NEK2 attenuated trastuzumab resistance, as evidenced by decreased cell viability and DNA replication and increased apoptosis, whereas NEK2 overexpression enhanced resistance to trastuzumab. Mechanistically, NEK2 promoted FN1 expression and activated PI3K/AKT signaling, while exogenous FN1 partially rescued the inhibitory effect of NEK2 knockdown on trastuzumab resistance. RNA immunoprecipitation, MeRIP-qPCR, and dual-luciferase reporter assays analyses further showed that WTAP-dependent N6-methyladenosine (m6A) modification at nucleotide 5882 of FN1 mRNA, followed by YTHDF1 recognition, enhanced FN1 mRNA stability and protein expression. Moreover, overexpression of either WTAP or YTHDF1 restored FN1 expression, AKT phosphorylation, and trastuzumab resistance in NEK2-silenced cells.

conclusionNEK2 promotes trastuzumab resistance in GC by enhancing WTAP/YTHDF1-dependent m6A regulation of FN1, thereby activating PI3K/AKT signaling. These findings suggest that NEK2 may represent a potential therapeutic target for overcoming trastuzumab resistance in GC.

Indexed as

Cell Cycle ProteinsDrug Resistance, NeoplasmFibronectinsNIMA-Related KinasesRNA Splicing FactorsStomach NeoplasmsTrastuzumabApoptosisCell Line, TumorGene Expression Regulation, NeoplasticHumansProto-Oncogene Proteins c-aktRNA MethylationSignal TransductionCell Cycle ProteinsFibronectinsNEK2 protein, humanNIMA-Related KinasesProto-Oncogene Proteins c-aktRNA Splicing FactorsTrastuzumabWTAP protein, humanFN1Gastric cancerm6ANEK2Trastuzumab resistance

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PMID42886303

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