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.
Highlights
The growing knowledge base of tumor genomics has led to never seen advances in the field of medical oncology. [1] The evolving molecularly targeted treatments of late-stage melanoma, gastro-intestinal stromal tumors, and non-small-cell lung cancer (NSCLC) exemplify these advances. [2,3,4]The fibroblast growth factor receptor (FGFR) family consists of four subtypes of transmembrane tyrosine kinase receptors that play an important role in cell growth, differentiation and angiogenesis via binding of up to 22 known different Fibroblast growth factor (FGF) family ligands. [5] Upon FGFR activation through dimerization of receptor monomers and transphosphorylation of kinase domain loop tyrosine residues cytoplasmatic downstream molecules contribute to carcinogenic events mediated by phosphatidylinositol 3-Kinase (PI3K)/AKT, STAT and RAS/MAPK pathways (Figure 1A). [5, 6]Anomalous signaling through FGFR can occur through overexpression of receptors, activating mutations, gene amplification, or by FGFR-containing translocations in wide array of solid tumors as discussed below
[13] Since FGFR3TACC3 fusion has been reported in numerous solid tumors including urothelial carcinoma, Non-small cell lung cancer (NSCLC), thyroid, and cervical carcinoma (Table 2)
The clinical relevance of FGFR3-TACC3 has been highlighted by 3 out of 4 partial responses among patients with tumors harboring FGFR3-TACC3 fusions treated with fibroblast growth factor receptor (FGFR) inhibitor JNJ-42756493
Summary
The growing knowledge base of tumor genomics has led to never seen advances in the field of medical oncology. [1] The evolving molecularly targeted treatments of late-stage melanoma, gastro-intestinal stromal tumors, and non-small-cell lung cancer (NSCLC) exemplify these advances. [2,3,4]The fibroblast growth factor receptor (FGFR) family consists of four subtypes of transmembrane tyrosine kinase receptors that play an important role in cell growth, differentiation and angiogenesis via binding of up to 22 known different FGF family ligands. [5] Upon FGFR activation through dimerization of receptor monomers and transphosphorylation of kinase domain loop tyrosine residues cytoplasmatic downstream molecules contribute to carcinogenic events mediated by PI3K/AKT, STAT and RAS/MAPK pathways (Figure 1A). [5, 6]Anomalous signaling through FGFR can occur through overexpression of receptors, activating mutations, gene amplification, or by FGFR-containing translocations in wide array of solid tumors as discussed below. Refractory solid tumors; on dose expansion subjects with sqNSCLC, gastric cancer, UC, endometrial cancer, multiple myeloma, or MPNs that have a tumor or malignancy that has NCT02393248 been evaluated and confirmed to harbor genetic alterations in FGF or FGFR genes Asian patients with advanced Non-small-cell lung cancer, urothelial cancer, gastric cancer, esophageal cancer or cholangiocarcinoma with FGFR gene mutation or Refractory solid tumors and lymphomas
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