TY - JOUR
T1 - Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis
AU - Ahangari, Farida
AU - Becker, Christine
AU - Foster, Daniel G.
AU - Chioccioli, Maurizio
AU - Nelson, Meghan
AU - Beke, Keriann
AU - Wang, Xing
AU - Justet, Aurelien
AU - Adams, Taylor
AU - Readhead, Benjamin
AU - Meador, Carly
AU - Correll, Kelly
AU - Lili, Loukia N.
AU - Roybal, Helen M.
AU - Rose, Kadi Ann
AU - Ding, Shuizi
AU - Barnthaler, Thomas
AU - Briones, Natalie
AU - DeIuliis, Giuseppe
AU - Schupp, Jonas C.
AU - Li, Qin
AU - Omote, Norihito
AU - Aschner, Yael
AU - Sharma, Lokesh
AU - Kopf, Katrina W.
AU - Magnusson, Björn
AU - Hicks, Ryan
AU - Backmark, Anna
AU - Dela Cruz, Charles S.
AU - Rosas, Ivan
AU - Cousens, Leslie P.
AU - Dudley, Joel T.
AU - Kaminski, Naftali
AU - Downey, Gregory P.
N1 - Publisher Copyright:
Copyright © 2022 by the American Thoracic Society.
PY - 2022/12/15
Y1 - 2022/12/15
N2 - Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration–approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-b (adenovirus transforming growth factor-b) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-b–stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial–mesenchymal transition, TGF-b, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial–mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
AB - Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two U.S. Food and Drug Administration–approved antifibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Objectives: Using an in silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. Methods: We investigated the antifibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: 1) in vitro in normal human lung fibroblasts; 2) in vivo in bleomycin and recombinant Ad-TGF-b (adenovirus transforming growth factor-b) murine models of pulmonary fibrosis; and 3) ex vivo in mice and human precision-cut lung slices from these two murine models as well as patients with IPF and healthy donors. Measurements and Main Results: In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone. Transcriptomic analyses of TGF-b–stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial–mesenchymal transition, TGF-b, and WNT signaling that was uniquely altered by saracatinib. Transcriptomic analysis of whole-lung extracts from the two animal models of pulmonary fibrosis revealed that saracatinib reverted many fibrogenic pathways, including epithelial–mesenchymal transition, immune responses, and extracellular matrix organization. Amelioration of fibrosis and inflammatory cascades in human precision-cut lung slices confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis. Conclusions: These studies identify novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment.
KW - Src family kinase
KW - idiopathic pulmonary fibrosis
KW - lung fibrosis
KW - preclinical models
KW - tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=85139249492&partnerID=8YFLogxK
U2 - 10.1164/rccm.202010-3832OC
DO - 10.1164/rccm.202010-3832OC
M3 - Article
C2 - 35998281
AN - SCOPUS:85139249492
SN - 1073-449X
VL - 206
SP - 1463
EP - 1479
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 12
ER -