Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGF\u03b21 induced lung and tumor fibrosis

Wentian Zhang,Sabastian Schmull,Hecheng Li,Yajie Zhang,Wenbo Wang,Yu Han,Tian Tu

doi:10.1038/s41419-020-02916-w

Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGF\u03b21 induced lung and tumor fibrosis

Wentian Zhang, Sabastian Schmull + Show 5 more

Open Access

https://doi.org/10.1038/s41419-020-02916-w

Copy DOI

Abstract

TGFβ1 signaling is a critical driver of collagen accumulation in pulmonary fibrotic diseases and a well-characterized regulator of cancer associated fibroblasts (CAF) activation in lung cancer. Myofibroblasts induced by TGFβ1 and other factors are key players in the pathogenesis of lung fibrosis and tumor. Tremendous attention has been gained to targeting myofibroblasts in order to inhibit the progression of fibrosis and myofibroblast-induced tumor progression and metastasis. Here we determined the therapeutic efficacy of simultaneously targeting PI3K and HDAC pathways in lung myofibroblasts and CAF with a single agent and to evaluate biomarkers of treatment response. CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and PI3K/AKT pathway. We investigated its effects in counteracting the activity of TGFβ1-induced myofibroblasts/CAF in regard to cell proliferation, migration, invasion, apoptosis in vitro antifibrosis efficiency in vivo. We found that CUDC-907 inhibited myofibroblasts/CAF cell proliferation, migration and apoptosis in a dose-dependent manner and caused cell cycle arrest at G1-S phase. CUDC-907 not only inhibited myofibroblasts markers expression, but also significantly inhibited the phosphorylation level of AKT, mTOR, Smad2/3, and promoted acetylation of histones. Furthermore, the observed inhibitory effect was also confirmed in bleomycin-induced mice lung fibrosis and nude mouse transplanted tumor model. Overall, these data suggest that dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for TGFβ1-induced lung and tumor fibrosis.

Highlights

Pathological lung fibrosis, and its promoting effects on tissue stiffness, is a major cause of human morbidity and mortality[1]
We found that CUDC-907 treatment significantly inhibited cellular proliferation in a time- and dosedependent manner and caused cell death at higher concentrations regardless of TGFβ1 stimulation (Fig. 1a–f)
We compared the anti-proliferate effect of CUDC-907 with PI3K inhibitor GDC0941 and histone deacetylases (HDACs) inhibitor Trichostatin A for CUDC-907 was designed based on their active ingredients (Fig. 1l)[19]

Summary

Introduction

Pathological lung fibrosis, and its promoting effects on tissue stiffness, is a major cause of human morbidity and mortality[1]. TGF-β1 signaling is both an initiator and a driver of lung stiffness because of extracellular matrix (ECM) deposition and myofibroblasts differentiation. 80% of the upregulated genes in lungs of Myofibroblasts, induced by TGFβ1-mediated signaling, exhibit continued activation in proliferation, anti-apoptosis, migration, invasion as well as expressing collagens and myofibroblasts markers such as α-SMA, FAP-α, and PDGFR etc[4,5,6]. Myofibroblasts in tumor are generally referred as tumor-associated fibroblasts or cancerassociated fibroblasts (CAF) and contribute as key fibro genic cells aggravating non-small cell lung cancer (NSCLC) growth and progression[7,8]. Intervening myofibroblast-induced pro-fibrotic and pro-tumorigenic activities using signaling inhibitor can be an interesting approach against fibrosis and cancer.

Methods

Results

Conclusion