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FGFR inhibitor resistance in cervical cancer: a role for integrin α2 and mTOR signalling

Nauf Bou Antoun1, Richard P Grose2,3, Anthony J Walker1

  • 1School of Life Sciences Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University London, Kingston-upon-Thames, United Kingdom.

Frontiers in Cell and Developmental Biology
|June 22, 2026
PubMed

Insights

Fibroblast growth factor receptor inhibitors (FGFRi) show promise for cervical cancer but resistance emerges. This study reveals resistance mechanisms involving integrin α2 (ITGA2) and focal adhesion kinase (FAK) signaling, suggesting new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cervical cancer necessitates effective systemic therapies due to late-stage diagnoses.
  • Fibroblast growth factor (FGF) signaling, via FGF receptors (FGFRs), is crucial for cell functions and implicated in cervical cancer progression.
  • Fibroblast growth factor receptor inhibitors (FGFRi) offer clinical potential but face challenges with therapeutic resistance.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving FGFR inhibitor resistance in human cervical cancer cell lines.
  • To identify key molecular players and signaling pathways involved in acquired resistance to FGFRi.
  • To explore potential combinatorial strategies for overcoming FGFRi resistance in cervical cancer.

Main Methods:

  • Transcriptomic analysis of parental and FGFRi-resistant cervical cancer cell lines (CaSki, HeLa, SiHa).
  • Protein interaction network analysis to identify central regulatory nodes.
  • Assessment of protein localization, activation status (e.g., phosphorylation), and signaling pathway engagement.

Main Results:

  • Downregulation of Pleckstrin Homology Like Domain Family A Member 1 (PHLDA1) and upregulation of Phospholipase C beta 4 (PLCB4) were observed in resistant cells.
  • Integrin α2 (ITGA2) was identified as a central node, with increased cytoplasmic localization and loss at cell-cell contacts in resistant cells.
  • Resistant cells showed activated focal adhesion kinase (FAK) and elevated S6 ribosomal protein (p-S6) phosphorylation, independent of FGFR, FAK, or mTORC1 inhibition.

Conclusions:

  • FGFR inhibitor resistance in cervical cancer is linked to integrin α2 (ITGA2)-focal adhesion kinase (FAK) signaling.
  • Activated mammalian target of rapamycin complex 1 (mTORC1) signaling, independent of AKT, contributes to resistance.
  • These findings suggest targeting ITGA2-FAK and mTOR pathways could overcome FGFRi resistance in cervical cancer.
Keywords:
FAKFGF(R)PHLDA1cervical cancerdrug resistanceintegrin α2mTOR

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