Dual Inhibition of HDAC and Tyrosine Kinase Signaling Pathways with CUDC-907 Inhibits TGFβ1 Induced Lung and Tumor Fibrosis

Abstract

Object: 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. Our aim was to determine 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. Method: 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 and antifibrosis efficiency in vivo. Result: 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. Conclusion: 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. Funding Statement: This study was financially supported by China National Nature Science Foundation (81871882), Science and Technology Commission of Shanghai Municipality Medical Guidance Science &Technology Support Project (16411966100), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20172005) and Shanghai Municipal Commission of Health and Family Planning Outstanding Academic Leaders Training Program (2017BR055). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: This protocol was approved by the Ethics Committee of Ruijin Hospital (KY 2018-104). All patients were enrolled after written informed consent.