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|Ref Type||Journal Article|
|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||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2012 Dec 15|
|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.|
|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||AZD4547||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 small cell carcinoma||sensitive||AZD4547||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 wild-type||lung cancer||decreased response||AZD4547||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 large cell carcinoma||sensitive||AZD4547||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 amp||lung non-small cell carcinoma||sensitive||AZD4547||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|