Göke, Friederike, Franzen, Alina, Hinz, Trista, Yoon, Petros, Marek4, Lindsay , Sharma, Rakesh, Bode, Maike , Maessenhausen, Anne, Lankat-Buttgereit, Brigitte, Göke, Antonia, Golletz, Carsten, Kirsten, Robert , Boehm, Diana , Vogel, Wenzel, Kleczko, Emily, Eagles-Soukup, Justin, Hirsch, Fred , Bremen, Tobias , Bootz, Friedrich, Schroeck, Andreas, Tan, Aik-Choon, Jimeno, Antonio , Heasley, Lynn and Perner, Sven (2015) FGFR1 expression levels predict BGJ398 Sensitivity of FGFR1-dependent head and neck Squamous cell cancers. Clinical Cancer Research, 21 (19). pp. 4356-4364. ISSN 15573265

Abstract

Purpose: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. Experimental Design: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. Results: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirtyone percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. Conclusions: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering fromHNSCC.

Item Type:	Article
Date Deposited:	13 Apr 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/24460