ArticleInternational journal of surgery (London, England)2026
Extracellular matrix-derived mechanical force induces CDK4/6 inhibitor resistance by inhibiting NEK10 dependent cell cycle regulation in breast cancer.
Article in International journal of surgery (London, England), 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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Abstract
backgroundBiomechanical signals play a pivotal role in tumor initiation and progression, with the extracellular matrix (ECM) acting as a key source of these signals. This study aims to investigate the role of ECM-derived biomechanical signals in mediating CDK4/6 inhibitor resistance in HR+, HER2- breast cancer. MATERIALS AND
methodsThis study utilized 3D Matrigel, collagen, and fibrin gels to examine the role of ECM-derived biomechanical signals in regulating CDK4/6 inhibitor resistance. Single-cell sequencing data from 23 breast cancer patients were analyzed to explore the core molecular mechanisms underlying this resistance. Transcriptomic analysis and Western blotting were conducted to assess the expression of the NEK10/p53/CDKN1A/CDK2 signaling pathway in breast cancers. Data from 1092 patients in TCGA were also incorporated, alongside a prognostic analysis of 25 clinical samples.
resultsECM-derived biomechanical signals suppressed CDK4/6 inhibitor-induced cell cycle arrest and senescence in breast cancer cells, promoting drug resistance. scRNA-seq and tumor tissue analysis identified NEK10 as a key downregulated kinase associated with resistance. Mechanistically, ECM-induced mechanical forces reduced NEK10 expression via a cytoskeleton-dependent pathway, leading to suppression of the NEK10/p53/CDKN1A axis and activation of CDK2 signaling. NEK10-deficient cells and organoids displayed enhanced resistance to Palbociclib, which was reversed by co-treatment with the CDK2 inhibitor. In vivo , combined inhibition of CDK4/6 and CDK2 significantly improved therapeutic efficacy in NEK10-low breast cancer.
conclusionThis study underscores the critical role of ECM-derived biomechanical forces in regulating CDK4/6 inhibitor resistance in breast cancer and identifies NEK10 as a potential therapeutic target for improving breast cancer treatment.
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