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.
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-β (adenovirus transforming growth factor-β) 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-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, 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-β (adenovirus transforming growth factor-β) 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-β-stimulated normal human lung fibroblasts identified specific gene sets associated with fibrosis, including epithelial-mesenchymal transition, TGF-β, 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 -