Fibroblast Growth Factor Receptor 1-4 Genetic Aberrations as Clinically Relevant Biomarkers in Squamous Cell Lung Cancer

Abstract

Fibroblast growth factor receptor (FGFR) inhibitors (FGFRis) are a potential therapeutic option for squamous non-small cell lung cancer (Sq-NSCLC). Because appropriate patient selection is needed for targeted therapy, molecular profiling is key to discovering candidate biomarker(s). Multiple FGFR aberrations are present in Sq-NSCLC tumors—alterations (mutations and fusions), amplification and mRNA/protein overexpression—but their predictive potential is unclear. Although FGFR1 amplification reliability was unsatisfactory, FGFR mRNA overexpression, mutations, and fusions are promising. However, currently their discriminatory power is insufficient, and the available clinical data are from small groups of Sq-NSCLC patients. Here, we focus on FGFR aberrations as predictive biomarkers for FGFR-targeting agents in Sq-NSCLC. Known and suggested molecular determinants of FGFRi resistance are also discussed.

Comprehensive analysis of the prognostic value and immune infiltration of FGFR family members in gastric cancer

“…Our result is consistent with a previous study which showed that the overexpression of FGFR1, FGFR2 and FGFR4 were detected in several GC cases by immunohistochemistry (IHC) staining, whereas FGFR3 was hardly detectable (34). FGFR1 (2%), FGFR2 (< 10%), FGFR4 (<2%) amplification was frequently reported in the GC sequencing studies (28,29,32). FGFR2 was the most investigated gene in FGFR family.…”

“…It has been commonly accepted that the FGFR family plays a critical role in biological development (e.g., embryogenesis, angiogenesis, tissue homeostasis) and in regulating physiological processes (e.g., migration, proliferation, and differentiation) ( 3 , 4 ). Therefore, abnormalities in FGF-FGFR signaling can lead to the development and progression of many cancers, including GC ( 27 – 29 ). Recently, many FGFR related drugs were invented and showed promising result in GC, including pan-FGFR inhibitors, selective FGFR inhibitors, FGFR antibodies and antibody drug conjugates ( 2 ).…”

Non‐small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours

“…FGFR1 amplifications are most commonly encountered in LUSC (11%) and only rarely in LUAD (0.7%); 18,19 the rate is significantly exaggerated in TTF1/p40 dual‐positive tumours compared to both LUAD and LUSC. The high rate of FGFR1 amplification may offer a unique approach to therapeutic targeting of these tumours, as FGF/FGFR signalling axis inhibition by tyrosine kinase inhibitors such as erdafitinib was shown to be an effective therapy in different tumour types, including NSCLC 19–21 …”

Treatment Considerations for Patients With Advanced Squamous Cell Carcinoma of the Lung

“…For example, recent analysis of FGFR aberrations indicate that while FGFR1 amplification does not seem to predict response to inhibitors, FGFR mRNA overexpression, mutations, and fusions are promising predictive biomarkers based on the limited clinical data currently available. 84 Recent phase I data have demonstrated that the pan-FGFR inhibitor, rogaratinib, is tolerable in patients with SCC tumors overexpressing FGFR mRNA, and has demonstrated signals of efficacy. 85 A phase II trial of rogaratinib in patients with advanced, pretreated SCC of the lung with tumors overexpressing FGFR mRNA is ongoing (NCT03762122).…”