Fig. 3

Strategies for targeting profibrotic signaling pathways. The two most important profibrotic signaling pathways are the hedgehog (Hh) pathway and the transforming growth factor-β (TGF-β) pathway. Binding of the Hh ligand to its receptor Patched (Ptc) enables the transmembrane protein Smoothened to activate the Gli transcription factors, ultimately leading to proliferation of cancer-associated fibroblasts (CAFs) and deposition of extracellular matrix components. Similarly, activation of the TGF-β pathway, mediated by the Smad proteins, activates CAFs and may cause tumor fibrosis. Several inhibitors of the Hh pathway have been developed, the most interesting being the Smoothened inhibitor IPI-926. The TGF-β pathway can be inhibited by angiotensin II receptor I blockers (ARBs) such as losartan, by halofuginone (a derivative of febrifugine), and by activating vitamin D receptor (VDR) signaling. Furthermore, high focal adhesion kinase (FAK) signaling in CAFs and parenchymal cancer cells may advance the formation of a fibrotic tumor microenvironment, and the FAK inhibitor defactinib is an efficient inhibitor of this pathway