The HIPPO signaling pathway was discovered two decades ago when it was first described as a regulator of tissue growth in Drosophila. Massive organ growth in Drosophila in response to the knockout of key pathway proteins resembled a “hippopotamus-like phenotype” inspiring the pathway name. The HIPPO pathway is conserved across species and in humans consists of the kinases Mst 1/2, Lats 1/2 and the adaptor proteins Sav 1/2, Mob 1/2. The signals transmitted through the HIPPO kinase cascade lead to the inhibition or activation of YAP1, which is the key downstream regulator controlling cell growth and survival at the transcription level, primarily through the interaction with proteins from the TEAD family. While the HIPPO-YAP1 axis was long understood as a pathway of embryonic development, its contribution to pathologies in the adult human organism was discovered later. Today, the deregulation of the pathway is linked to diseases such as neurological- and cardiac dysfunction, immune diseases and cancer. For cancer, aberrant HIPPO-YAP1 activity is found in multiple tumor types and can be the result of alterations on the genome level for genes encoding either HIPPO pathway proteins or YAP1 itself. Alternatively, aberrant YAP1 activity can occur in response to cancer treatments through mechanisms of epigenetic regulation or signaling pathway crosstalk. The aberrant activation of YAP1 in persister cells, a small population of cells that remains viable during anticancer therapies, is thought to be at the origin of tumor relapse. The question hence arises as how to best drug this pathway. The first YAP1 inhibitor described was Verteporfin, a molecule used in photodynamic therapy. Verteporfin inhibits YAP1 by increasing its cytoplasmic retention and degradation but its effect is not specific. A more direct way of inhibiting aberrant YAP1 activation was obtained through targeting the interaction between YAP1 and its partner protein TEAD by peptide compounds. These molecules bind TEAD proteins at their interface with YAP1 and disrupt YAP1-TEAD protein-protein interaction, however, they are not cell permeable. A more recent approach still was the identification of small molecule inhibitors targeting the central lipid pocket of TEAD proteins. Such molecules block YAP1-TEAD dependent gene transcription and show efficacy in cell and animal systems. Therefore, targeting HIPPO-YAP1 has become possible and is a promising approach for new cancer therapies.

HIPPO-YAP1: A neglected pathway in cancer therapy

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.