Abstract P212: Systems biology-guided indication selection to inform the clinical development of a novel TEAD inhibitor
Authors: Sanchez-Martin Marta , Syed Sakeena , Frosch Hyejin , Turcotte Chelsea , Amidon Benjamin , McGovern Karen , Ecsedy Jeffrey , Zhang Michelle X. 
Published: December 2021

Abstract
TEAD transcription factors are the final effectors of the Hippo pathway, a signaling cascade comprising multiple tumor suppressors (NF2, MST1/2, LATS1/2) critical in regulating proliferation, survival, and tissue homeostasis. Activated Hippo signaling suppresses TEAD-dependent transcription through the phosphorylation and degradation of TEAD co-activators YAP1 and TAZ in the cytosol. Consistently, genetic alterations in NF2, LATS1/2, YAP1 or TAZ lead to aberrant TEAD activation and are implicated in tumor initiation, progression, and therapeutic resistance in cancer. Here we present a unique systems biology approach integrating genomic, transcriptional and tissue-based analysis, to inform clinical development, indication and patient selection biomarkers for a novel inhibitor of TEAD being developed by Ikena. To identify cancers dependent on TEAD activity, tumor types were evaluated based on the cumulative incidence of genetic alterations in Hippo pathway genes including NF2, LATS1/2, YAP1, TAZ and others. This novel analysis pointed to a subset of tumors with high frequency of genetic alterations driving aberrant Hippo signaling including mesothelioma and NSCLC. This same subset was found to highly express a transcriptional signature indicative of YAP1/TEAD-dependency, confirming increased activation of TEAD transcription and pointing to the dependency of these tumors on TEAD activity. A proprietary IHC method was used to further assess YAP1/TAZ activation by assessing expression of either protein in the nucleus in multiple tumor tissue microarrays. Tissue-based analysis showed high YAP1 nuclear expression in tumors with frequent genetic alterations and high YAP1/TEAD-signature. Mesothelioma in particular ranks top among these indications, due to high frequency of NF2 deficiency and other Hippo pathway alterations. Consistently, TEAD inhibition showed single agent activity in two xenograft models of mesothelioma with NF2 deficiency and LAST1/2 alterations respectively. Hippo pathway alterations frequently co-occur with mutations in other oncogenic signaling pathways, e.g. EGFR. Importantly, YAP1/TAZ have been implicated in acquired resistance to targeted therapies in cancer including EGFR inhibitors in EGFR mutant tumors. Indeed, PDX models derived from patients who relapsed on osimertinib treatment showed high YAP1 protein expression in the nucleus. In addition, combination of TEAD and EGFR inhibitors induced apoptosis in vitro and greater antitumor activity than either drug as a single agent in vivo in EGFR mutant cancer models. In summary, the integration of multi-disciplinary bioinformatics, pharmacologic and tissue-based approaches enabled the identification of cancer types with high dependency on Hippo signaling. Moreover, these studies support the for monotherapy and combination of TEAD inhibitors with other targeted therapies including EGFR inhibitors. Altogether this unique approach has identified cancer patients who may benefit from TEAD inhibition and has informed the clinical development plan of a novel TEAD inhibitor.
Citation Format: Marta Sanchez-Martin, Sakeena Syed, Hyejin Frosch, Chelsea Turcotte, Benjamin Amidon, Karen McGovern, Jeffrey Ecsedy, Michelle X. Zhang. Systems biology-guided indication selection to inform the clinical development of a novel TEAD inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P212.