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Background <p>Acquired resistance to anlotinib, a multi-targeted tyrosine kinase inhibitor, severely limits its long-term efficacy in non-small cell lung cancer (NSCLC). The extracellular matrix (ECM) is a critical component of the tumor microenvironment known to mediate drug resistance, but the key regulators within the ECM driving anlotinib resistance remain elusive.</p> Methods <p>We performed a preliminary, exploratory transcriptomic analysis using a publicly available dataset to identify differentially expressed genes between anlotinib-resistant and wild-type NSCLC cells. Exploratory enrichment analysis suggested ECM organization as a potentially altered process, from which FREM1 was selected as a top candidate for further validation. Functional roles of FREM1 were investigated using siRNA knockdown in resistant cell lines, followed by CCK-8, EdU, flow cytometry, wound healing, and Transwell assays. Underlying mechanisms were probed via Western blot and immunofluorescence.</p> Results <p>FREM1 was significantly upregulated in anlotinib-resistant cells. Its knockdown enhanced the anti-tumor effect of anlotinib in resistant cells, leading to reduced proliferation, migration, and invasion while promoting apoptosis. Mechanistically, silencing FREM1 potently reversed the anlotinib-induced suppression of key ECM components, including Collagen I, Collagen IV, Fibronectin, and Laminin α5.</p> Conclusion <p>Our study identifies FREM1 as a candidate mediator of anlotinib resistance in NSCLC via regulation of ECM remodeling. Targeting the FREM1-ECM axis subject to independent validation represents a promising strategy to overcome resistance.</p>

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FREM1 promotes anlotinib resistance in non-small cell lung cancer through regulation of extracellular matrix organization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Yi Dong,
  • Jingjing Zhang,
  • Yuyang Zhao,
  • Jiwei Zhao,
  • Fan Xu

摘要

Background

Acquired resistance to anlotinib, a multi-targeted tyrosine kinase inhibitor, severely limits its long-term efficacy in non-small cell lung cancer (NSCLC). The extracellular matrix (ECM) is a critical component of the tumor microenvironment known to mediate drug resistance, but the key regulators within the ECM driving anlotinib resistance remain elusive.

Methods

We performed a preliminary, exploratory transcriptomic analysis using a publicly available dataset to identify differentially expressed genes between anlotinib-resistant and wild-type NSCLC cells. Exploratory enrichment analysis suggested ECM organization as a potentially altered process, from which FREM1 was selected as a top candidate for further validation. Functional roles of FREM1 were investigated using siRNA knockdown in resistant cell lines, followed by CCK-8, EdU, flow cytometry, wound healing, and Transwell assays. Underlying mechanisms were probed via Western blot and immunofluorescence.

Results

FREM1 was significantly upregulated in anlotinib-resistant cells. Its knockdown enhanced the anti-tumor effect of anlotinib in resistant cells, leading to reduced proliferation, migration, and invasion while promoting apoptosis. Mechanistically, silencing FREM1 potently reversed the anlotinib-induced suppression of key ECM components, including Collagen I, Collagen IV, Fibronectin, and Laminin α5.

Conclusion

Our study identifies FREM1 as a candidate mediator of anlotinib resistance in NSCLC via regulation of ECM remodeling. Targeting the FREM1-ECM axis subject to independent validation represents a promising strategy to overcome resistance.