Reference Detail

Ref Type

Journal Article

PMID

(23082000)

Authors

Zhang J, Zhang L, Su X, Li M, Xie L, Malchers F, Fan S, Yin X, Xu Y, Liu K, Dong Z, Zhu G, Qian Z, Tang L, Schöttle J, Zhan P, Ji Q, Kilgour E, Smith PD, Brooks AN, Thomas RK, Gavine PR

Title

Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	18	24	2012 Dec 15	6658-67	Clin Cancer Res

URL

Abstract Text

To investigate the incidence of FGFR1 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 FGFR1-amplified patient-derived tumor xenograft (PDTX) models.A range of assays was used to assess the translational relevance of FGFR1 amplification and AZD4547 treatment including in vitro lung cell line panel screening and pharmacodynamic (PD) analysis, FGFR1 FISH tissue microarray (TMA) analysis of Chinese NSCLC (n = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547.The incidence of FGFR1 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 FGFR1 (GI(50) = 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 in vivo, and antitumor efficacy correlated well with FGFR1 FISH score and protein expression level.This study provides novel epidemiologic data through identification of FGFR1 gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple FGFR1-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 FGFR1.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	lung cancer	sensitive	Fexagratinib	Preclinical	Actionable	In a preclinical study, AZD4547 inhibited proliferation of lung cancer cell lines harboring FGFR1 amplification in culture and induced tumor regression in xenograft models (PMID: 23082000).	23082000
FGFR1 amp	lung large cell carcinoma	sensitive	Fexagratinib	Preclinical	Actionable	In a preclinical study, AZD4547 inhibited proliferation of a large cell lung cancer cell line harboring FGFR1 amplification in culture and induced tumor regression in xenograft models (PMID: 23082000).	23082000
FGFR1 wild-type	lung cancer	decreased response	Fexagratinib	Preclinical	Actionable	In a preclinical study, FGFR1 non-amplified lung cancer cell lines demonstrated reduced sensitivity to AZD4547 induced growth inhibition in culture and in xenograft models (PMID: 23082000).	23082000
FGFR1 amp	lung small cell carcinoma	sensitive	Fexagratinib	Preclinical	Actionable	In a preclinical study, AZD4547 inhibited proliferation of a small cell lung cancer cell line harboring FGFR1 amplification in culture (PMID: 23082000).	23082000
FGFR1 amp	lung non-small cell carcinoma	sensitive	Fexagratinib	Preclinical - Pdx	Actionable	In a preclinical study, AZD4547 inhibited FGFR1 signaling and resulted in tumor regression in patient-derived xenograft models of non-small cell lung carcinoma harboring FGFR1 amplification, wild-type for EGFR, K-Ras and negative for EML4-ALK fusion (PMID: 23082000).	23082000