Abstract 5466: The role of fibroblast growth factor receptor 1 (FGFR1) in small cell lung cancer (SCLC).

Abstract

Abstract Background: Although molecularly-targeted treatment options for solid tumors have advanced in recent years, there remains a significant therapeutic need for SCLC, which constitutes 12% of all lung cancers and carries a poor prognosis. FGFR1, a transmembrane tyrosine kinase receptor encoded by the FGFR1 gene in chromosome 8p12 is involved in cell cycle, differentiation, survival, apoptosis, and angiogenesis. In SCLC, FGF/FGFR pathway is known to induce proliferation, disrupt apoptosis and mediate chemo-resistance. Pharmacologic FGFR inhibition in SCLC reduces proliferation and increases apoptosis both in vitro and in vivo. We and others have reported high copy number gains (CNG) in cytogenetic bands encoding FGFR1 in SCLC suggesting that FGFR1 may be driver mutation and a potential therapeutic target in SCLC. In this study we further characterize FGFR1 as a therapeutic target in SCLC. Methods: Thirteen SCLC cell lines, 16 SCLC patient samples, and 14 SCLC tumors from commercially available tissue microarray (TMA) were screened for copy number alterations using array comparative genomic hybridization (aCGH) and focal FGFR1 amplifications using fluorescence in situ hybridization (FISH). In the cell lines, FGFR1 exons were sequenced from genomic DNA, mRNA expression evaluated using real-time polymerase chain reaction and protein expression determined semi-quantitatively using western blot. Growth inhibition assays were performed using PD173074, a selective FGFR inhibitor and standard cytotoxic agents (cisplatin and etoposide) to determine the correlation between FGFR1 expression and drug sensitivity. Results: CNG was detected in 10/16 (63%) patient samples and in 5/14 (36%) of tumors from TMA (range 4-9 copies per cell). 5/13 (38%) of cell lines demonstrated CNG, but we found no FGFR1 mutations or focal amplifications in SCLC cell lines. FGFR1 mRNA expression did not correlate with CNG and the FGFR1 protein expression was unrelated to the mRNA expression. FGFR1 CNG predicted sensitivity to PD173074 with cell lines carrying higher copy numbers being more sensitive. No such correlation was detected between FGFR1 mRNA expression and PD173074 sensitivity. Higher FGFR1 mRNA expression was associated with etoposide resistance. Conclusion: FGFR1 protein expression in SCLC cell lines is unrelated to copy number alterations and mRNA expression. CNG of 8p12 region which encodes FGFR1 predicts sensitivity to PD173074, a selective FGFR inhibitor. Citation Format: Anish Thomas, Jih-Hsiang Lee, Yisong Wang, Ziedulla Abdullaev, Lola Saidkhodjaeva, Svetlana D. Pack, Giuseppe Giaccone. The role of fibroblast growth factor receptor 1 (FGFR1) in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5466. doi:10.1158/1538-7445.AM2013-5466