The Hippo pathway is a critical signal transduction pathway that regulates cell fate, polarity, proliferation, and survival, as well as organ size and tissue homeostasis. Numerous non-canonical oncogenes and tumor suppressors, including KRAS, NRAS, p53, PTEN, PIK3CA, EGFR, and β-catenin, can affect Hippo signaling in multiple cancer types. Key nodes in the pathway, such as NF2 and LATS1/2, are also highly dysregulated in cancer. Activated Hippo signaling correlates with poor patient outcomes in a number of cancers. Moreover, the Hippo pathway has been shown to promote immune evasion via multiple mechanisms.

When the Hippo pathway is inactivated, the transcriptional coactivators YAP and TAZ are stabilized, translocate into the cell nucleus and bind to the TEAD transcription factor to drive transcription of multiple genes involved in tumor initiation and progression, cancer metastasis, and therapeutic resistance. It has been demonstrated that acquired Tyrosine Kinase Inhibitor (TKI) resistance is dependent upon increased YAP/TAZ-TEAD transcription via direct activation to bypass BRAF. Inhibition of TEAD can lead to restored TKI sensitivity.

Clinical proof-of-concept studies for Ikena’s TEAD inhibitor program will be performed in cancers with loss of function mutations known to drive disease. Ikena believes that their TEAD inhibitors have the potential to be active both as single-agent therapy and in combination with other standard of care oncology agents to overcome therapeutic resistance. In addition, translational studies are ongoing to identify additional tumor types likely to be Hippo pathway-driven and dependent on TEAD function.