Fibroblast Growth Factor Receptors (FGFRs) are a family of proteins found on the surface of cells throughout the body. These receptors act as docking stations for specific signaling molecules called Fibroblast Growth Factors (FGFs). When an FGF binds to its FGFR, it initiates a series of internal cellular communications. This interaction is fundamental for cells to receive and interpret messages from their environment. FGFRs participate in a wide array of the body’s basic biological processes.
Function of FGFR in the Body
When a Fibroblast Growth Factor (FGF) protein binds to its corresponding Fibroblast Growth Factor Receptor (FGFR) on the cell’s exterior, it activates a cascade of signals within the cell. This activation prompts the cell to carry out specific functions. The signals triggered by FGFRs regulate cell growth, orchestrate cell division, and guide cells in becoming specialized for particular roles in the body. They also contribute to angiogenesis, the formation of new blood vessels.
These receptors hold particular significance during the early stages of life, influencing embryonic development by guiding the formation of bones, skin, and nerve tissues. As individuals mature, FGFRs continue their work, contributing to the body’s ability to repair damaged tissues and facilitate wound healing. There are four primary types of these receptors, known as FGFR1, FGFR2, FGFR3, and FGFR4, each possessing unique roles within this protein family. Different versions of these proteins exist across various tissues, interacting with a range of growth factors to ensure diverse biological responses.
FGFR Alterations and Human Disease
Problems can arise when the normal signaling of Fibroblast Growth Factor Receptors (FGFRs) is disrupted by genetic alterations. These changes in the genetic code can take several forms, including mutations (single changes in the gene’s instructions), amplifications (too many copies of an FGFR gene), or fusions and rearrangements (parts of the FGFR gene breaking off and attaching to other genes). These alterations often lead to a “gain-of-function,” causing the FGFR to be constantly active, even without a growth factor signal.
In the context of cancer, such gain-of-function alterations can result in uncontrolled cell growth and division, contributing to tumor development. FGFR alterations are observed in various cancer types:
- Bladder cancer: FGFR3 mutations are frequently found in non-muscle-invasive tumors.
- Cholangiocarcinoma: FGFR2 fusions are a common alteration in the bile ducts.
- Lung cancer: Non-small cell lung cancer can exhibit FGFR1 amplifications.
- Breast cancer: May show amplifications in FGFR1 and FGFR2.
- Other cancers: Endometrial and gastric cancers also show FGFR alterations.
Beyond cancer, FGFR alterations can disrupt normal development, leading to a range of skeletal and developmental conditions. Achondroplasia, the most common form of short-limbed dwarfism, is caused by specific mutations in the FGFR3 gene that result in an overly active receptor, hindering bone growth from cartilage. Craniosynostosis syndromes involve the premature fusion of skull bones, causing a misshapen head and distinctive facial features. These conditions, such as Crouzon, Pfeiffer, and Apert syndromes, are often linked to gain-of-function mutations in FGFR1, FGFR2, and FGFR3, leading to an overactive receptor that promotes early bone fusion in the skull.
Identifying FGFR Alterations
When Fibroblast Growth Factor Receptor (FGFR) alterations are suspected, doctors use specialized tests to identify these genetic changes. This process involves genomic testing, often performed on tissue samples, such as a tumor biopsy. These tests determine if an FGFR alteration is present, which can influence treatment decisions.
Next-Generation Sequencing (NGS) is an advanced method that analyzes a large portion of a person’s DNA simultaneously. NGS can detect various FGFR alterations, including mutations, amplifications, and fusions, by reading millions of DNA fragments in parallel. This approach provides a detailed genetic profile from a single sample.
Immunohistochemistry (IHC) uses antibodies to detect the presence and amount of specific proteins in tissue samples. For FGFR, IHC can reveal overexpression of the FGFR protein, which might indicate a gene amplification. Fluorescence in situ hybridization (FISH) is employed to visualize specific genetic rearrangements. FISH uses fluorescent probes that attach to particular segments of DNA, allowing identification of gene fusions or amplifications by observing how these segments light up under a microscope.
Therapeutic Targeting of FGFR
Targeted therapy is a specialized approach to treating diseases driven by specific molecular changes, such as those involving Fibroblast Growth Factor Receptors (FGFRs). Unlike traditional chemotherapy, which broadly affects rapidly dividing cells, targeted therapies precisely inhibit the faulty protein driving the disease. This approach focuses treatment on the underlying cause of the condition.
FGFR inhibitors are a class of drugs developed to block the abnormal activity of altered FGFR proteins. These medications interfere with the receptor’s signaling pathway, turning off continuous growth signals that contribute to disease progression. For instance, erdafitinib is an approved FGFR inhibitor for certain patients with urothelial carcinoma who have specific FGFR2 or FGFR3 alterations. Pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusions or other rearrangements.
These inhibitors are a form of precision medicine, most effective in patients whose conditions are directly linked to an identified FGFR alteration. Before starting treatment, genetic testing confirms the presence of these specific FGFR changes, ensuring the therapy is appropriate for the individual. Futibatinib is another FGFR inhibitor that targets FGFR1 through FGFR4, demonstrating broad inhibitory activity against various FGFR genomic aberrations.