Richard P. Grose

Development and Characterization of Three Novel FGFR Inhibitor Resistant Cervical Cancer Cell Lines to Help Drive Cervical Cancer Research

Primary or acquired resistance to therapeutic agents is a major obstacle in the treatment of cancer patients. Cervical cancer is the fourth leading cause of cancer deaths among women worldwide and, despite major advances in cancer screening and treatments, many patients with advanced stage cervical cancer have a high recurrence rate within two years of standard treatment, with drug resistance being a major contributing factor. The development of cancer cell lines with acquired resistance to therapeutic agents can facilitate the comprehensive investigation of resistance mechanisms, which cannot be easily performed in clinical trials. This study aimed to create three novel and robust cervical cancer cell lines (HeLa, CaSki, and SiHa) with acquired resistance to a fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor (PD173074). All three drug-resistant (DR) cell lines overexpressed FGFR1, FGFR2, FGF2, FGF4, and FGF7 proteins that were also localized to the nucleus. In addition, the DR cells had a significantly more aggressive phenotype (more migratory and proliferative, less apoptotic) compared to the parental cell lines. These novel DR cervical cancer cells are a critical tool for understanding the molecular mechanisms underpinning drug resistance and for the identification of potential cervical cancer biomarkers. Moreover, the availability of such DR cell lines may facilitate the development of more effective therapeutic strategies using FGFR inhibitors in combination with other agents that target pathways responsible for acquired resistance to FGFR inhibitors.

FGF signalling facilitates cervical cancer progression

Cervical cancer is one of the most frequently diagnosed cancers in women worldwide. While cervical cancer is caused by human papillomavirus (HPV), not all females infected with HPV develop the disease, suggesting that other factors might facilitate its progression. Growing evidence supports the involvement of the fibroblast growth factor receptor (FGFR) axis in several cancers, including gynecological. However, for cervical cancer, the molecular mechanisms that underpin the disease remain poorly understood, including the role of FGFR signaling. The aim of this study was to investigate FGF(R) signaling in cervical cancer through bioinformatic analysis of cell line and patient data and through detailed expression profiling, manipulation of the FGFR axis, and downstream phenotypic analysis in cell lines (HeLa, SiHa, and CaSki). Expression (protein and mRNA) analysis demonstrated that FGFR1b/c, FGFR2b/c, FGFR4, FGF2, FGF4, and FGF7 were expressed in all three lines. Interestingly, FGFR1 and 2 localized to the nucleus, supporting that nuclear FGFRs could act as transcription factors. Importantly, 2D and 3D cell cultures demonstrated that FGFR activation can facilitate cell functions correlated with invasive disease. Collectively, this study supports an association between FGFR signaling and cervical cancer progression, laying the foundations for the development of therapeutic approaches targeting FGFR in this disease.