Expected and unexpected effects after systemic inhibition of Hippo transcriptional output in cancer

Abstract Hyperactivation of YAP/TAZ, the Hippo pathway downstream effectors, is common in human cancer. The requirement of YAP/TAZ for cancer cell survival in preclinical models, prompted the development of pharmacological inhibitors that suppress their transcriptional activity. However, systemic YAP/TAZ inhibition may sometimes have unpredictable patient outcomes, with limited or even adverse effects because YAP/TAZ action is not simply tumor promoting but also tumor suppressive in some cell types. Here, we review the role of the Hippo pathway in distinct tumor cell populations, discuss the impact of inhibiting Hippo output on tumor growth, and examine current developments in YAP/TAZ inhibitors.