Fibroblast Growth Factor Receptors (FGFRs) are a family of proteins that act as cellular switches, receiving signals from outside the cell and transmitting them inward. The genes that provide the instructions for making these receptors are FGFR1, FGFR2, FGFR3, and FGFR4. These receptors are receptor tyrosine kinases, meaning they activate a cascade of chemical reactions when triggered. Mutations in the genes coding for these proteins disrupt this communication process, leading to aberrant signaling pathways within the cell. This disruption can cause the receptor to be constantly active or improperly regulated, severely impacting normal biological functions. The resulting cellular miscommunication is the underlying cause of a spectrum of human conditions, ranging from developmental disorders to various types of cancer.
The Normal Role of FGFR Proteins
FGFR proteins are positioned on the cell surface, functioning like antennae waiting to receive signals from specific messenger molecules called Fibroblast Growth Factors (FGFs). When an FGF molecule binds to its corresponding receptor, it causes the receptor to pair up with another, triggering a process called autophosphorylation inside the cell. This activation initiates a cascade of internal signals that regulate several fundamental cellular activities. These downstream pathways control cell proliferation, differentiation, and survival, ensuring tissues grow and repair correctly.
The signaling network generated by FGFRs is particularly important during embryonic development, where it orchestrates the formation of organs and limbs. In mature organisms, FGFR signaling is involved in tissue repair, wound healing, and the maintenance of tissue balance. This signaling is particularly important in the skeleton, where it controls the conversion of cartilage into bone, a process called ossification.
FGFR Mutations and Skeletal Disorders
Most FGFR-related skeletal disorders are caused by a “gain-of-function” mutation, which locks the receptor into an “on” position, constantly signaling the cell even without the presence of a growth factor. This overactivity leads to the premature or abnormal differentiation of cells, especially in bone and cartilage tissue. The resulting pathology is typically an over-inhibition of growth or an acceleration of bone fusion.
Achondroplasia, the most common form of human dwarfism, is a classic example resulting from a gain-of-function mutation in FGFR3. In this condition, the overactive FGFR3 receptor excessively restricts the proliferation and differentiation of chondrocytes, the cells responsible for forming cartilage at the growth plates. This results in severely shortened long bones and characteristic short-limbed stature.
Another group of conditions, known as craniosynostoses, involves the premature fusion of the cranial sutures, the flexible joints between the skull bones. Syndromes like Apert, Crouzon, and Pfeiffer are often linked to activating mutations in FGFR1 or FGFR2. The constant signaling from the mutated receptor accelerates the ossification process, causing the skull bones to fuse too early and potentially leading to abnormal head shapes and facial structures.
FGFR Mutations in Cancer Development
FGFR mutations drive oncogenesis by providing a permanent, unregulated signal for cell growth and division. These oncogenic alterations are broadly classified into three types: gene amplifications, point mutations, and gene fusions. FGFR alterations are found in approximately 7% of all tumors, with amplifications being the most frequent type.
Gene fusions occur when a portion of an FGFR gene breaks off and joins with another gene, creating a hybrid protein that is constitutively active. These fusions, particularly involving FGFR2, are a common driver in up to 15% of intrahepatic cholangiocarcinoma, a form of bile duct cancer. Point mutations, where a single base pair change results in an overactive receptor, are particularly prevalent in urothelial (bladder) cancer, where activating FGFR3 mutations can be found in up to 80% of non-muscle invasive cases.
Gene amplification involves a cancer cell making too many copies of an FGFR gene, often seen in solid tumors like breast and lung cancer. FGFR1 amplification is a recognized alteration in a subset of breast cancers and squamous non-small cell lung carcinomas. Regardless of the specific alteration type, the shared biological effect is the unchecked activation of downstream pathways that promote tumor cell survival, migration, and proliferation.
Therapeutic Approaches Targeting FGFR
Treating conditions caused by FGFR mutations requires specialized and condition-specific interventions.
Skeletal Disorders
For skeletal disorders like craniosynostosis, the primary approach is surgical, involving complex procedures to separate the prematurely fused skull bones. These interventions are often performed in infancy or early childhood to allow for normal brain growth and development. In cases of achondroplasia, management focuses on orthopedic care and addressing complications associated with skeletal structure.
Cancer
For cancers driven by FGFR alterations, a precision medicine approach utilizes targeted therapies known as FGFR inhibitors. These small-molecule drugs work by blocking the active site of the mutated receptor, effectively shutting down the continuous growth signal driving the tumor. Specific inhibitors, such as erdafitinib, are approved for use in certain advanced urothelial cancers with susceptible FGFR3 mutations. Other drugs, like pemigatinib, target FGFR2 fusions in cholangiocarcinoma.