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.

TGFβ1 信号传导是肺纤维化疾病中胶原蛋白积累的关键驱动因素，并且是肺癌中癌症相关成纤维细胞 (CAF) 激活的公认调节剂。由 TGFβ1 和其他因子诱导的肌成纤维细胞是肺纤维化和肿瘤发病机制中的关键参与者。靶向肌成纤维细胞以抑制纤维化和肌成纤维细胞诱导的肿瘤进展和转移的进展引起了极大的关注。在这里，我们确定了用单一药剂同时靶向肺肌成纤维细胞和 CAF 中的 PI3K 和 HDAC 通路的治疗效果，并评估治疗反应的生物标志物。CUDC-907 是一流的化合物，可作为 HDAC 和 PI3K/AKT 通路的双重抑制剂。我们研究了它在抵消 TGFβ1 诱导的肌成纤维细胞/CAF 活性方面​​的作用，这些活性涉及细胞增殖、迁移、侵袭、凋亡 体外 体内 抗纤维化效率。我们发现CUDC-907以剂量依赖性方式抑制肌成纤维细胞/CAF细胞增殖、迁移和凋亡，并导致细胞周期停滞在G1-S期。CUDC-907不仅抑制肌成纤维细胞标志物的表达，还显着抑制AKT、mTOR、Smad2/3的磷酸化水平，促进组蛋白乙酰化。此外，在博莱霉素诱导的小鼠肺纤维化和裸鼠移植肿瘤模型中也证实了观察到的抑制作用。总体，