Therapeutic Targeting of FGFR Signaling in Head and Neck Cancer

Abstract

Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most prevalent cancer worldwide, with an annual incidence of 600,000 new cases. Despite advances in surgery, chemotherapy, and radiotherapy, the overall survival for HNSCC patients has not been significantly improved over the past several decades. Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) genomic alterations are frequently detected in HNSCC, including amplification, activating mutation, and chromosomal rearrangement. Among them, FGFR1 amplification, FGF amplifications, and FGFR3 mutations are the most prevalent. In addition, FGF/FGFR expression has also been observed in most HNSCCs. However, the prognostic value of FGF/FGFR aberrations remains unclear, especially for gene amplification and overexpression. Nonetheless, FGF/FGFR has been a promising target for HNSCC treatment, and recent preclinical studies demonstrate the potential of the combination treatment regimens involving FGFR inhibitors on HNSCC. Therefore, there are a number of FGFR inhibitors currently in clinical trials for the treatment of head and neck cancers.

A Phase II Trial of Nintedanib in Patients with Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma: In-Depth Analysis of Nintedanib Arm from the KCSG HN 15-16 TRIUMPH Trial

“…According to The Cancer Genome Atlas (TCGA) data [ 6 ], amplifications and mutation of FGFR1 , FGFR2 , and FGFR3 are reported to occur in 10%, 2%, and 2% of patients with human papillomavirus–negative cancers, respectively. Other studies have reported FGFR genomic alterations, most frequently focal amplifications in FGFR1 and FGFR3 mutations, in approximately 8.9%-37.3% of HNSCC [ 4 , 7 , 8 ]. Because they are one of the most prevalent receptor tyrosine kinase mutations in HNSCC, the FGFR pathway may serve as a potential, promising therapeutic target [ 7 ].…”

The diverse dependence of galectin-1 and -8 on multivalency for the modulation of FGFR1 endocytosis

“…Binding of FGFs to D2-D3 domains initiates FGFR1 dimerization and conformational changes within the intracellular portion of the receptor, resulting in the activation of TK and subsequent FGFR1 autophosphorylation [ 9 , 10 ]. FGFR1 signaling, by controlling fundamental cellular processes like apoptosis, differentiation, division and motility, is critical for the human life at all its stages and its dysregulation is observed in numerous tumors including lung, breast, head and neck and urothelial cancers [ 10 – 17 ]. Several regulatory mechanisms are engaged in balancing FGFR1 signals such as endocytosis, phosphatases, negative regulatory proteins and feedback signaling [ 18 ].…”

FGFR1/2/3‐rearranged carcinoma of the head and neck: expanded histological spectrum crossing path with high‐risk HPV in the sinonasal tract

“…1 In the head and neck, FGFR pathway alterations are frequently detected in squamous cell carcinomas (SCC), most commonly in the forms of FGFR1 amplification (5-30%), FGF amplification (20-25%) and FGFR3 activating mutations (5.8-62%). 2 Oncogenic FGFR rearrangements are rare and mainly represented by FGFR3::TACC3 fusions in approximately 3% of SCC. In addition, FGFR1::PLAG1 fusions were detected in pleomorphic adenoma (PA) and carcinomas ex PA, [2][3][4][5][6] being particularly enriched in myoepithelial carcinomas ex PA. 4,7 However, these tumours are generally considered PLAG1-instead of FGFR1-driven, given that the latter's kinase domain is typically absent in the fusion transcript.…”

“…2 Oncogenic FGFR rearrangements are rare and mainly represented by FGFR3::TACC3 fusions in approximately 3% of SCC. In addition, FGFR1::PLAG1 fusions were detected in pleomorphic adenoma (PA) and carcinomas ex PA, [2][3][4][5][6] being particularly enriched in myoepithelial carcinomas ex PA. 4,7 However, these tumours are generally considered PLAG1-instead of FGFR1-driven, given that the latter's kinase domain is typically absent in the fusion transcript. 4 Interestingly, several reports of SCC have concurrently harboured human papillomavirus (HPV) and FGFR3::TACC3 fusions.…”

“…Activation of the fibroblastic growth factor receptor (FGFR) signalling is a well‐recognised oncogenic mechanism in various human cancers with a growing number of selective inhibitors recently developed for the most susceptible tumours, such as intrahepatic cholangiocarcinoma (10–20% harbouring FGFR2 fusions) and urothelial carcinoma (10–60% with FGFR3 mutations, 6% with FGFR3 fusions) 1 . In the head and neck, FGFR pathway alterations are frequently detected in squamous cell carcinomas (SCC), most commonly in the forms of FGFR1 amplification (5–30%), FGF amplification (20–25%) and FGFR3 activating mutations (5.8–62%) 2 . Oncogenic FGFR rearrangements are rare and mainly represented by FGFR3 :: TACC3 fusions in approximately 3% of SCC.…”