Abstract

<div>Abstract<p><b>Purpose:</b> To investigate the incidence of <i>FGFR1</i> amplification in Chinese non–small cell lung cancer (NSCLC) and to preclinically test the hypothesis that the novel, potent, and selective fibroblast growth factor receptor (FGFR) small-molecule inhibitor AZD4547 will deliver potent antitumor activity in NSCLC <i>FGFR1–</i>amplified patient-derived tumor xenograft (PDTX) models.</p><p><b>Experimental Design:</b> A range of assays was used to assess the translational relevance of <i>FGFR1</i> amplification and AZD4547 treatment including <i>in vitro</i> lung cell line panel screening and pharmacodynamic (PD) analysis, <i>FGFR1</i> FISH tissue microarray (TMA) analysis of Chinese NSCLC (<i>n</i> = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547.</p><p><b>Results:</b> The incidence of <i>FGFR1</i> amplification within Chinese patient NSCLC tumors was 12.5% of squamous origin (6 of 48) and 7% of adenocarcinoma (5 of 76). AZD4547 displayed a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified <i>FGFR1</i> (GI<sub>50</sub> = 0.003–0.111 μmol/L). AZD4547 induced potent tumor stasis or regressive effects in four of five FGFR1-amplified squamous NSCLC PDTX models. Pharmacodynamic modulation was observed <i>in vivo</i>, and antitumor efficacy correlated well with <i>FGFR1</i> FISH score and protein expression level.</p><p><b>Conclusions:</b> This study provides novel epidemiologic data through identification of <i>FGFR1</i> gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple <i>FGFR1</i>-amplified squamous lung cancer PDTX models to show tumor stasis or regression effects using a specific FGFR inhibitor (AZD4547). Thus, the translational science presented here provides a strong rationale for investigation of AZD4547 as a therapeutic option for patients with squamous NSCLC tumors harboring amplification of <i>FGFR1</i>. <i>Clin Cancer Res; 18(24); 6658–67. ©2012 AACR</i>.</p></div>

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