Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network,
cancer genetics/genomics of
FGF receptors (FGFRs), and FGFR-targeted
therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGFβ, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in
lung cancer and
estrogen receptor (ER)-positive
breast cancer, and that of FGFR2 in diffuse-type
gastric cancer and
triple-negative breast cancer.
Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and
alveolar rhabdomyosarcoma, as with FGFR3 in
multiple myeloma and
peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in
glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial
uterine cancer and
melanoma, and similar FGFR3 mutations in invasive
bladder tumors, and FGFR4 mutations in
rhabdomyosarcoma.
Dovitinib,
Ki23057,
ponatinib, and
AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments.
Dovitinib,
ponatinib, and
AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted
therapy is a promising strategy for the treatment of refractory
cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted
therapeutics in the era of
personalized medicine.