Abstract
The Hippo pathway is a critical regulator of cell and organ growth and has emerged as a target for therapeutic intervention in cancers. Its signaling is thought to play an important role in various physiological processes including homeostasis and tissue regeneration. To date there has been limited information about potential pharmacology-related (on-target) safety liabilities of Hippo pathway inhibitors in the context of cancer indications. Herein, we review data from human genetic disorders and genetically engineered rodent models to gain insight into safety liabilities that may emerge from the inhibition of Hippo pathway. Germline systemic deletion of murine Hippo pathway effectors (Yap, Taz, and Teads) resulted in embryonic lethality or developmental phenotypes. Mouse models with tissue-specific deletion (or mutant overexpression) of the key effectors in Hippo pathways have indicated that, at least in some tissues, Hippo signaling may be dispensable for physiological homeostasis; and appears to be critical for regeneration upon tissue damage, indicating that patients with underlying comorbidities and/or insults caused by therapeutic agents and/or comedications may have a higher risk. Caution should be taken in interpreting phenotypes from tissue-specific transgenic animal models since some tissue-specific promoters are turned on during development. In addition, therapeutic agents may result in systemic effects not well-predicted by animal models with tissue-specific gene deletion. Therefore, the development of models that allows for systemic deletion of Yap and/or Taz in adult animals will be key in evaluating the potential safety liabilities of Hippo pathway modulation. In this review, we focus on potential challenges and strategies for targeting the Hippo pathway in cancers.
Highlights
The Hippo signaling pathway has been identified as a key regulator of cell and organ growth and various physiological processes including normal homeostasis and tissue regeneration
Yesassociated protein (YAP) and TAZ share approximately 50% amino acid sequence identity with a similar domain organization, and each contains a TEAD binding domain (Moroishi et al, 2015). They are transcriptional coactivators of TEADs, and nuclear YAP/TAZ-TEAD complexes activate expression of target genes that are involved in cell proliferation, apoptosis, differentiation/regeneration, and tissue homeostasis
We summarize data from human genetic disorders as well as various mouse models for the key Hippo pathway effectors (Yap, Taz and Teads) and implications in targeting this pathway in diseases
Summary
The Hippo pathway is a critical regulator of cell and organ growth and has emerged as a target for therapeutic intervention in cancers. To date there has been limited information about potential pharmacologyrelated (on-target) safety liabilities of Hippo pathway inhibitors in the context of cancer indications. Mouse models with tissue-specific deletion (or mutant overexpression) of the key effectors in Hippo pathways have indicated that, at least in some tissues, Hippo signaling may be dispensable for physiological homeostasis; and appears to be critical for regeneration upon tissue damage, indicating that patients with underlying comorbidities and/or insults caused by therapeutic agents and/or comedications may have a higher risk. The development of models that allows for systemic deletion of Yap and/or Taz in adult animals will be key in evaluating the potential safety liabilities of Hippo pathway modulation.
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