Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis

Ahangari, Farida; Becker, Christine; Foster, Daniel G.; Chioccioli, Maurizio; Nelson, Meghan; Beke, Keriann; Wang, Xing; Justet, A.; Adams, Taylor; Readhead, Benjamin; Meador, Carly; Correll, Kelly A.; Lili, Loukia N.; Roybal, H.M.; Rose, Kadi-Ann; Ding, Shuizi; Bärnthaler, Thomas; Briones, Natalie; DeIuliis, Giuseppe; Schupp, Jonas C.; Qin, Li; Omote, Norihito; Aschner, Yael; Sharma, Lokesh; Kopf, Katrina W; Magnusson, Björn; Hicks, Ryan; Backmark, Anna; Cruz, Charles S. Dela; Rosas, Iván O.; Cousens, Leslie P.; Dudley, Joel T.; Kaminski, Naftali; Downey, Gregory P.

doi:10.1164/rccm.202010-3832oc

Cited by 44 publications

(26 citation statements)

References 68 publications

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“…CMap analysis of scRNAseq of IPF bronchial brushings suggested that src inhibition can reverse the observed pro-fibrotic transcriptional changes in IPF bronchial airway basal cells 50 . Moreover, CMap analysis of IPF transcriptional profiles and the nintedanib and pirfenidone corresponding transcriptional signatures, indicated src inhibition as the strongest connection 51 . As shown here, CMap analysis of the TGFβ-induced Tks5 +/- LFs profile identified, among established and promising others, src inhibition as a possible treatment to limit LF invasion (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…6). Src inhibition has been previously shown to attenuate BLM-induced pulmonary fibrosis 51-53 , while the Src inhibitor Saracatanib 51 has entered clinical trials ( NCT04598919 ). Therefore, targeting podosome formation, an inherent pathogenic LF property as shown here, as well as LF interactions with the ECM including invasion, are very promising therapeutic targets in pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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SRC-mediated and TKS5-enabled podosome formation is an inherent property of IPF fibroblasts, promoting ECM invasion and pulmonary fibrosis

Barbayianni

Kanellopoulou

Fanidis

et al. 2023

Preprint

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The activation and accumulation of lung fibroblasts (LFs), resulting in aberrant deposition of collagens and other extracellular matrix (ECM) components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of IPF patients and bleomycin (BLM)-treated mice, correlating with increased collagen type I alpha 1 chain (COL1A1) expression. The profibrotic milieu, TGFβ, as well as a stiff Col1a1-rich acellular fibrotic ECM, were found to induce TKS5 expression and the formation of prominent podosome rosettes in LFs, culminating in increased ECM invasion. Podosomes were retained ex vivo in the absence of any stimulation, indicating that the formation of TKS5-enabled podosomes is an inherent property of IPF LFs. Remarkably, haploinsufficient Tks5+/- mice were relatively resistant to BLM-induced pulmonary fibrosis. Disease protection was largely attributable to diminished podosome formation in LFs and decreased ECM invasion, thus indicating TKS5-enabled and podosome-mediated ECM invasion as a major pathogenic mechanism in pulmonary fibrosis. Expression profiling revealed an ECM-podosome cross talk, and pharmacologic connectivity map analysis suggested several inhibitors that could prevent podosome formation and thus pulmonary fibrosis. Among them, inhibition of src kinase was shown to potently attenuate podosome formation in LFs, ECM invasion, as well as pulmonary fibrosis in post BLM precision cut lung slices, suggesting that pharmacological targeting of TKS5-enabled podosome formation is a very promising therapeutic option in pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

SRC-mediated and TKS5-enabled podosome formation is an inherent property of IPF fibroblasts, promoting ECM invasion and pulmonary fibrosis

Barbayianni

Kanellopoulou

Fanidis

et al. 2023

Preprint

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“…Two studies examined the antifibrotic effects of novel therapies on TGF-β treated human lung fibroblasts (HLFs), bleomycininduced fibrotic murine models and human precision cut lung slices (hPCLS). 58,59 In the first, the inhibition of Src kinases with saracatinib inhibited profibrotic gene expression and myofibroblast transformation in HLFs. In murine models, epithelial-mesenchymal transition and extracellular matrix organization were attenuated.…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

“…These findings were validated in hPLCS where fibrosis was ameliorated with saracatinib which was either equal or superior to pirfenidone and nintedanib in all models. 58 The second study generated and examined the effect of MRG-229, a mimic of the micro-RNA miR-29 and found that it reduced fibrosis in HLFs and lung slice culture, and counteracted profibrotic genes in mouse models. 59…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

Contemporary Concise Review 2022: Interstitial lung disease

Smith

Jenkins

2023

Respirology

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SUMMARY OF KEY POINTS Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis. The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments. Newly identified circulating biomarkers are associated with disease progression and mortality. Deep learning and machine learning may increase accuracy in the interpretation of CT scans. Novel treatments have shown benefit in phase 2 clinical trials. Hospitalization with COVID‐19 is associated with residual lung abnormalities in a substantial number of patients. Inequalities exist in delivering and accessing interstitial lung disease specialist care.

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“…In this issue of the Journal , Ahangari and colleagues (pp. 1463–1479 ) present the results of an impressive amount of work to identify a potential antifibrotic molecule, saracatinib, a selective Src (Src protooncogene, nonreceptor tyrosine kinase) kinase inhibitor originally developed as anticancer drug, and to validate its efficacy in blocking fibrogenic processes across different in vitro , in vivo , and ex vivo models of pulmonary fibrosis ( 7 ). In the context of a drug repurposing strategy, the authors applied an innovative data-driven approach to explore potential connections among a set of 32 preselected compounds and more than 700 diseases via comparison of their transcriptomic signatures.…”

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confidence: 99%