Hippo/YAP pathway for targeted therapy
Malignant pleural mesothelioma (MPM) is molecularly characterized by loss of function or mutations in the neurofibromin 2 (NF2) and the cyclin-dependent kinase inhibitor 2 genes. NF2 activates a cascade of kinases, called Hippo pathway, which downregulates Yes associated protein (YAP) function as transcription co-activator for TEA domain transcription factors (TEAD). In the absence of functional NF2, the expression of genes essential for cell cycling such as survivin is increased. New therapeutic strategies aimed at interfering with YAP activity include inhibition of hedgehog pathway, which downregulates the YAP protein, verteporfin, which inhibits the assembly of a functional YAP-TEAD transcription factor, and interference with thrombin and lysophosphatidic acid (LPA) receptors downstream signalling, since upon agonist binding they activate YAP.