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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Innovation Center China, AstraZeneca R&D, Shanghai, China.
Jingchuan
J
Zhang
Lin
L
Zhang
Xinying
X
Su
Ming
M
Li
Liang
L
Xie
Florian
F
Malchers
ShuQiong
S
Fan
XiaoLu
X
Yin
YanPing
Y
Xu
Kunji
K
Liu
Zhengwei
Z
Dong
Guanshan
G
Zhu
Ziliang
Z
Qian
Lili
L
Tang
Jakob
J
Schöttle
Ping
P
Zhan
Qunsheng
Q
Ji
Elaine
E
Kilgour
Paul D
PD
Smith
A Nigel
AN
Brooks
Roman K
RK
Thomas
Paul R
PR
Gavine
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1