Fig. 1

Chromosomal localization of the patient’s amplified genes CDK4, MDM2, FRS2, CCND2, FGF6 and FGF23 and FGF-FGFR signaling pathways cross talk with cell-cycle pathway. A Relevant (targeted) amplified genes are detected in chromosome 12, and their specific localization are demonstrated in the figure. MDM2 was also amplified and localizes to chromosome 12, but it was not considered druggable. B The binding of ligands to receptors triggers the conformational changes of FGFRs, leading to dimerization and activation of FGFRs. Activated FGFRs phosphorylate FRS2, and FRS2 binds to the SH2 domain-containing adaptor protein GRB2. GRB2 will subsequently bind to SHC, SOS and activates downstream the RAS-RAF-MEK-ERK pathway responsible for proliferation and survival. GRB2 also binds with another adaptor protein, GAB1, which has a YXXM motif responsible for the recruitment of p85, leading to activate the PI3K-AKT-mTOR pathway. The PI3K-AKT-mTOR pathway is responsible for proliferation, migration, angiogenesis, cap-dependent mRNA translation and inhibits apoptosis. Cyclin D1/D2/D3 is also activated by upstream RAS-MAPK and AKT-mTOR pathways. Cyclin D binds with CDK4/6 to promote RB phosphorylation, which depresses the E2F transcription factor to drive the expression of genes that promote cell cycle progression. The FGF-FGFR signaling pathway also activates downstream JAK-STAT and PLCγ-PKC pathways, both are responsible for various oncogenic phenotypes. Amplified genes from current case (FGF6, 23, FRS2, Cyclin D2, and CDK4) are showing in italic, and therapies (palbociclib and lenvatinib) are showing in the red boxes. FGF fibroblast growth factor, FGFR fibroblast growth factor receptor, FRS2 FGFR substrate 2, GAB1 GRB2 associated binding protein 1, GRB2 growth factor receptor-bound 2, SOS son of sevenless; PKC protein kinase C, PLCγ phospholipase C gamma, HSPG heparan sulfate proteoglycan