Fibroblast Growth Factor Receptors (FGFRs) are a group of proteins that play important roles in the human body. They function as cellular switches, receiving external signals that direct fundamental processes like cell growth, division, and repair. These receptors are widely distributed throughout the body, participating in the maintenance and proper functioning of various tissues and organs. When these signaling pathways operate normally, they contribute to healthy development and tissue regeneration.
However, sometimes FGFRs can malfunction, leading to uncontrolled cellular activity. This dysregulation can result from genetic changes, such as mutations or fusions within the FGFR genes. When FGFRs become overactive or “stuck on,” they can continuously signal cells to grow and divide without proper regulation. This uncontrolled proliferation is a hallmark of several diseases, particularly certain types of cancers. FGFR inhibitors are a class of medications specifically designed to address these malfunctions by targeting the aberrant activity of these receptors.
Understanding FGFR and Its Role
Fibroblast Growth Factor Receptors (FGFRs) are a family of receptor tyrosine kinases, a type of protein found on the surface of cells. There are four main types of FGFRs in humans: FGFR1, FGFR2, FGFR3, and FGFR4. These receptors act as crucial communication points, binding to specific signaling molecules called Fibroblast Growth Factors (FGFs).
Upon binding with FGFs, FGFRs undergo a change that activates their internal signaling machinery. This activation initiates a cascade of events inside the cell, relaying external growth and survival messages. These pathways are integral for diverse biological functions, including embryonic development, tissue repair, and the formation of new blood vessels.
In diseases like cancer, genetic alterations (gene amplifications, point mutations, or fusions) can disrupt normal FGFR function. These changes cause FGFRs to become continuously active, even without FGFs, providing a constant “grow” signal. This promotes unchecked cell proliferation and survival, a hallmark of many cancers. For instance, FGFR mutations are observed in a notable percentage of solid tumors, with higher frequencies in specific cancer types like urothelial carcinoma, breast cancer, and cholangiocarcinoma.
How FGFR Inhibitors Work
FGFR inhibitors represent a type of targeted therapy, designed to specifically interfere with the malfunctioning FGFR signaling pathway. Unlike traditional chemotherapy, which often affects all rapidly dividing cells, these inhibitors selectively block aberrant signals from overactive FGFRs. This targeted approach helps minimize harm to healthy cells.
The mechanism of action involves blocking the activity of the FGFR protein. They achieve this by binding to a specific site on the FGFR, often the ATP-binding pocket within the receptor’s kinase domain. By occupying this site, inhibitors prevent the FGFR from initiating the signaling cascade that drives cell growth and survival.
Imagine the FGFR as a “switch” that is stuck in the “on” position due to a genetic defect, constantly telling the cell to grow. An FGFR inhibitor acts like a specific “lock” that fits into this faulty switch, preventing it from sending its continuous growth signals. By blocking these signals, FGFR inhibitors can slow down or stop the proliferation of cancer cells that depend on the faulty FGFR pathway for their survival. This interruption ultimately leads to the suppression of tumor growth and can induce tumor cell death.
Clinical Applications and Approved Therapies
FGFR inhibitors are a specialized class of drugs used to treat specific types of cancers where genetic alterations in FGFRs are identified. These therapies are often reserved for patients whose tumors exhibit particular FGFR gene fusions, mutations, or amplifications, detected through genetic testing (biomarker testing). This ensures treatment is precisely matched to the patient’s tumor biology.
One notable application is in urothelial carcinoma (a type of bladder cancer), where erdafitinib (Balversa) is approved for adult patients with locally advanced or metastatic disease harboring susceptible FGFR3 genetic alterations. This approval is for patients whose disease has progressed after at least one prior systemic therapy.
In cholangiocarcinoma (bile duct cancer), several FGFR inhibitors are approved. Pemigatinib (Pemazyre) and Futibatinib (Lytgobi) are indicated for previously treated, advanced or metastatic cholangiocarcinoma with specific FGFR2 fusions or rearrangements. Identifying the precise FGFR alteration in a patient’s tumor is crucial before starting treatment.
Navigating Treatment: Side Effects and Monitoring
While FGFR inhibitors offer targeted treatment for specific cancers, they can cause a range of side effects. Many are “on-target” effects, occurring because FGFRs also play roles in healthy tissues. One common side effect is hyperphosphatemia, an elevation of phosphate levels in the blood, which occurs because FGFR inhibition can affect kidney function related to phosphate regulation. This can be managed through dietary modifications, such as a low-phosphate diet, and sometimes with phosphate-lowering medications.
Other frequently observed side effects include changes to the skin, hair, and nails. Patients may experience dry skin, hair loss (alopecia), and nail disorders such as nail separation (onycholysis) or inflammation around the nails (paronychia). Hand-foot syndrome, characterized by redness, swelling, and pain on the palms and soles, can also occur. Gastrointestinal issues like diarrhea, nausea, constipation, and changes in taste are also reported.
Ocular side effects are another consideration, including dry eyes, blurred vision, and in some cases, more serious retinal changes. Regular monitoring is crucial during FGFR inhibitor treatment to manage these potential effects. This often includes routine blood tests to check phosphate levels and regular eye exams to detect and address any vision changes promptly. Healthcare professionals work with patients to individualize treatment plans, which may involve dose adjustments or temporary interruptions to manage side effects and maintain quality of life.