What are Fibroblast Growth Factors (FGFs)?
Fibroblast Growth Factors (FGFs) are a family of proteins that play crucial roles in various biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, and angiogenesis. They exert their biological effects by binding to specific receptors known as FGF receptors (FGFRs), triggering downstream signaling pathways that influence cellular behavior.
How are FGFs Linked to Cancer?
The dysregulation of FGF/FGFR signaling pathways is frequently observed in many types of cancer. Aberrant activation can occur through multiple mechanisms, such as gene amplification, mutations, or overexpression of FGFs and FGFRs. This abnormal signaling promotes cancer cell proliferation, survival, invasion, and angiogenesis, contributing to tumor growth and metastasis.
What Cancers are Most Associated with FGF Dysregulation?
FGF and FGFR dysregulation has been implicated in various cancers, including breast cancer, lung cancer, bladder cancer, gastric cancer, and prostate cancer. For instance, FGFR1 amplification is commonly seen in breast and lung cancers, whereas FGFR2 mutations are often found in gastric cancers.
- Cell Proliferation: FGFs bind to FGFRs, activating downstream signaling pathways such as MAPK and PI3K/AKT, which drive cell division.
- Survival: FGFs enhance the survival of cancer cells by protecting them from apoptosis.
- Angiogenesis: FGFs promote the formation of new blood vessels, supplying nutrients and oxygen to the tumor.
- Invasion and Metastasis: FGFs facilitate the invasion of cancer cells into surrounding tissues and distant organs.
- FGFR Inhibitors: Small molecule inhibitors targeting FGFRs have shown efficacy in preclinical and clinical studies. Examples include erdafitinib and pemigatinib.
- Monoclonal Antibodies: These antibodies specifically bind to FGFs or FGFRs, blocking their interaction and downstream signaling.
- Ligand Traps: Soluble FGFRs act as decoys, sequestering FGFs and preventing them from binding to cell surface receptors.
- Resistance: Cancer cells may develop resistance to FGFR inhibitors via secondary mutations or activation of alternative pathways.
- Side Effects: FGFR inhibitors can cause side effects such as hyperphosphatemia and mucositis, necessitating careful management.
- Biomarker Identification: Identifying reliable biomarkers to select patients who will benefit from FGFR-targeted therapies is crucial yet challenging.
What is the Future of FGF/FGFR-Targeted Therapies?
The future holds promise with ongoing research aimed at overcoming current challenges. Combination therapies that target multiple pathways, improved patient selection through biomarkers, and the development of next-generation inhibitors are areas of active investigation. Personalized medicine approaches, incorporating genetic and molecular profiling, are expected to enhance the efficacy and safety of FGF/FGFR-targeted treatments.
