Abstract 2474: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo

The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. The Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2. These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member. In addition, this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment. To target this oncogenic pathway we identified novel small molecule inhibitors that selectively bind to TEAD and disrupt their interaction with YAP and TAZ thereby downregulating YAP- and TAZ-dependent transcription. These inhibitors prevent TEAD palmitoylation which is essential for the interaction between YAP and TEAD. Furthermore, they inhibit in vitro proliferation of YAP-dependent (i.e. Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines. An attraction of targeting this pathway is that many differentiated cells and tissues do not rely on the Hippo pathway, but notable exceptions have been demonstrated with tissue specific mouse knockouts in the bile duct and kidney podocytes. Importantly, our compounds did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology. Subsequent experiments in vivo demonstrate these inhibitors downregulate YAP-dependent genes in human tumor xenografts after oral dosing. In addition, these inhibitors exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses. These data demonstrate the potential for targeting this critical pathway in cancers with small molecules. Additional studies to identify tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress. Citation Format: Ben Amidon, Sakeena Syed, Jill Cavanaugh, Hyejin Frosch, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo C. Castro. Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2474.