Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma

TO THE EDITOR Transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) are central mediators of fibrosis, and their overexpression contributes to the pathophysiology of scleroderma, chiefly by inducing the overproduction of extracellular matrix proteins (ECM) by dermal fibroblasts (Gay et al., 1989; Sargent et al., 2010; Bhattacharyya et al., 2012). TGF-β also promotes the differentiation of dermal fibroblasts into myofibroblasts, which are key mediators of scleroderma (Abraham et al., 2007). Thus, targeting this pathway is a reasonable strategy to treat a variety of fibrotic diseases including scleroderma, for which current treatment options are limited. Herein we explore the potential of novel mTOR inhibition as a means to block the pro-fibrotic effects of TGF-β. Recent studies have suggested a functional role of mTOR in fibrotic diseases and autoimmunity (Ong et al., 2007; Fried et al., 2008; Su et al., 2009; Raychaudhuri and Raychaudhuri, 2014). This pathway is initiated by cytokines and growth factors that induce phosphorylation of Akt(Thr308) and its downstream mediators mTORC1, p70S6K1, and 4E-BP1. In addition to mTORC1, mTOR is now known to comprise a second multi-protein complex, mTORC2, which positively regulates the activity of mTOR through phosphorylation of AktSer473 (Bhagwat et al., 2011). Blockade of mTORC1 has already been attempted as a treatment for scleroderma without much understanding about its molecular mechanism (Fried et al., 2008; Su et al., 2009; Yoshizaki et al., 2010). Such strategies focused only on mTORC1 and did not account for the contributions of mTORC2 (Bhagwat et al., 2011). To increase the effectiveness of mTOR blockade, dual inhibitors targeting both mTORC1 and mTORC2 have now been developed (Bhagwat et al., 2011). Herein, we demonstrate that dual mTOR blockade can more effectively inhibit the pro-fibrotic effects of TGF-β and PDGF. These have therapeutic implications for scleroderma and other TGF-β dominant fibrotic diseases.