FGFR3-TACC3 fusion in solid tumors: mini review

Abstract

Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.

A metabolic function of FGFR3-TACC3 gene fusions in cancer

“…We discovered FGFR3-TACC3 (F3-T3) gene fusions in 3% of human glioblastoma 4 . Subsequent studies reported similar frequencies of F3-T3 in many other cancers, thus qualifying F3-T3 as one of the most recurrent fusions across all tumor types 5,6 . F3-T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors but the downstream oncogenic signaling remains largely unknown 2,4–6 .…”

Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

“…4D) NCI-H1581, A-204, HuH-7, NCI-H716, and RT112) with a variety of different FGFR alterations (Supplementary Table S4). In addition to gene amplification or overexpression, FGFRs can be constitutively activated by chromosomal rearrangement (7,28). However, FGFR gene translocations are rarely present in existing xenograft models derived from cancer cell lines.…”

ASP5878, a selective FGFR inhibitor, to treat FGFR3‐dependent urothelial cancer with or without chemoresistance

“…FGFR3 fusion genes are observed in 3% (3/114) of muscle‐invasive urothelial cancer . Therefore, clinical trials of FGFR inhibitors in urothelial cancer harboring FGFR3 fusion genes or point mutations are ongoing . The clinical relevance of FGFR3‐TACC3 has been suggested by the clinical report of JNJ‐42756493, a pan‐FGFR inhibitor, which exerts three out of four partial responses among patients with tumors harboring FGFR3‐TACC3 fusion genes .…”

“…(11) Therefore, clinical trials of FGFR inhibitors in urothelial cancer harboring FGFR3 fusion genes or point mutations are ongoing. (12) The clinical relevance of FGFR3-TACC3 has been suggested by the clinical report of JNJ-42756493, a pan-FGFR inhibitor, which exerts three out of four partial responses among patients with tumors harboring FGFR3-TACC3 fusion genes. (13) In a subset of urothelial cancer patients harboring FGFR3 gene alternation (FGFR3 fusion gene and point mutation) treated with BGJ398, the overall response rate in 25 evaluable patients was 36% and included one unconfirmed complete response and eight partial responses.…”