Angiomotin stabilization by tankyrase inhibitors antagonizes constitutive TEAD-dependent transcription and proliferation of human tumor cells with Hippo pathway core component mutations

// Albino Troilo 1,* , Erica K. Benson 1,* , Davide Esposito 1 , Rachel-Ann A. Garibsingh 1 , E. Premkumar Reddy 1 , Sathish Kumar Mungamuri 1 and Stuart A. Aaronson 1 1 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Stuart A. Aaronson, email: // Keywords : tankyrase inhibitors, TEAD, YAP, angiomotin, tumor cell proliferation Received : February 24, 2016 Accepted : March 26, 2016 Published : April 29, 2016 Abstract The evolutionarily conserved Hippo inhibitory pathway plays critical roles in tissue homeostasis and organ size control, while mutations affecting certain core components contribute to tumorigenesis. Here we demonstrate that proliferation of Hippo pathway mutant human tumor cells exhibiting high constitutive TEAD transcriptional activity was markedly inhibited by dominant negative TEAD4, which did not inhibit the growth of Hippo wild-type cells with low levels of regulatable TEAD-mediated transcription. The tankyrase inhibitor, XAV939, identified in a screen for inhibitors of TEAD transcriptional activity, phenocopied these effects independently of its other known functions by stabilizing angiomotin and sequestering YAP in the cytosol. We also identified one intrinsically XAV939 resistant Hippo mutant tumor line exhibiting lower and less durable angiomotin stabilization. Thus, angiomotin stabilization provides a new mechanism for targeting tumors with mutations in Hippo pathway core components as well as a biomarker for sensitivity to such therapy.