FGFR1 amplifications in squamous cell carcinomas of the lung: diagnostic and therapeutic implications

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is a type 4 receptor tyrosine kinase. The receptor and its ligands play an important role in development and physiology. However, constitutive activation of FGFR1 by gene amplification, translocation or mutation is associated with various malignancies as, for example, breast cancer or myeloproliferative diseases. We have recently reported that FGFR1 amplification occurs in 20% of pulmonary squamous cell carcinomas, and preclinical tests have shown that these alterations are therapeutically tractable. These findings make FGFR1 amplification a potential biomarker for lung cancer treatment. Squamous cell carcinomas of the lung are characterized by an uneven FGFR1 gene copy number distribution. Therefore, fluorescence in situ hybridization assays need to address focality and heterogeneity of FGFR1 in these tumors. Here, we review our proposal for a reading and evaluation strategy. Furthermore, we highlight the emerging landscape of clinical trials with selective and unselective FGFR inhibitors and provide first response data from early clinical trials.

Keywords: FISH; Lung cancer; fibroblast growth factor receptor 1 (FGFR1); squamous cell carcinoma.

Figures

Figure 1

Fluorescence in situ hybridization for detection of FGFR1 amplification in pulmonary squamous cell carcinomas. A. In this tumor, FGFR1 (green) and chromosome 8 (CEN8, orange) copies are more or less evenly distributed. Only occasionally, microclusters are seen (arrow); B. Heterogeneity occurs frequently in these tumors. Beside tumor cells with normal or only slight increase in copy numbers, there are many tumor cell nuclei with tight clusters of amplified FGFR1, some of which are indicated by arrows. Note that the occurrence of FGFR1 clusters is not necessarily related to the size of the nuclei.