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

Cervical cancer is the fourth most common cancer among women worldwide and is often diagnosed at advanced stages, highlighting the need for effective systemic therapies, including those targeting key cancer-related pathways. Fibroblast growth factor (FGF) signalling plays a critical role in cell biology, activating FGF receptors (FGFRs) to regulate proliferation, migration and apoptosis. Aberrant activation of the pathway contributes to tumour progression in many cancers, including cervical cancer. FGFR inhibitors (FGFRi) have shown clinical promise but are limited by emergence of therapeutic resistance. Here, we describe mechanisms underpinning FGFRi resistance in three human cervical cancer cell lines (CaSki, HeLa, and SiHa). Transcriptomic analysis identified several genes differentially expressed between parental and resistant lines, including downregulation of Pleckstrin Homology Like Domain Family A Member 1 (PHLDA1) and upregulation of Phospholipase C beta 4 (PLCB4), changes that associate with a metastatic phenotype. Protein interaction network analysis revealed integrin α2 (ITGA2) as a putative central node. Increased cytoplasmic localisation of ITGA2 and concomitant loss at cell- cell contacts, alongside focal adhesion kinase (FAK) activation was observed in PD173074 resistant cells. Moreover, resistant cell lines exhibited elevated S6 ribosomal protein (p-S6) phosphorylation, which persisted despite inhibition of FGFR, FAK or mammalian target of rapamycin complex 1 (mTORC1). Collectively, these findings suggest that FGFR inhibitor resistance in cervical cancer is associated with ITGA2–FAK signalling and AKT-independent mTOR activation, offering potential for overcoming therapeutic resistance via combinatorial treatment strategies.