One of the leading causes of death worldwide, in both men and women, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review covers both intrinsic and acquired resistance and gives a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put up by treatments, and, like “satellite navigation”, find alternative routes by which to carry on their “journey” to cancer progression.

The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R axis is critical during normal tissue development, homeostasis and repair. Therefore, it is not surprising that substantial evidence also pinpoints the involvement of aberrant FGFR signalling in disease, including tumourigenesis. FGFR aberrations in cancer include mutations, gene fusions, and amplifications as well as corrupted autocrine/paracrine loops. Indeed, many clinical trials on cancer are focusing on targeting the FGF/FGFR axis, using selective FGFR inhibitors, nonselective FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies and some have already been approved for the treatment of cancer patients. The heterogeneous tumour microenvironment and complexity of FGFR signalling may be some of the factors responsible for the resistance or poor response to therapy with FGFR axis-directed therapeutic agents. In the present review we will focus on the structure and function of FGF(R)s, their common irregularities in cancer and the therapeutic value of targeting their function in cancer.

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.

One of the leading causes of death worldwide, in both man and woman, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt)/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review will cover both intrinsic and acquired resistance and give a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put by treatments, and like “satellite navigation”, find alternative routes to carry on their “journey” to cancer progression.

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.