The Hippo pathway as an antitumor target: time to focus on

The Hippo signaling governs the expression of genes critically important for cell proliferation and survival. The components of this pathway are considered antitumor drug targets. However, the design of Hippo inhibitors is a challenge given the complexity of the network and redundancy of its elements.

We review the current state-of-the-art in the structure of the Hippo pathway, the microenvironment-induced extracellular cues, the strategies to design pharmacological instruments for inactivation of the Hippo signaling using small molecular weight modulators, as well as the results of initial clinical trials.

One special characteristic of the Hippo signaling is the adverse role of phosphorylation: opposite to classical kinase cascades that activate the transcription factors, the Hippo kinases retain their partners in a transcriptionally inactive state. Therefore, approaches for pharmacological or genetic inhibition of Hippo protein kinases are counterproductive. The developing alternatives such as disruption of protein-protein interactions or PROTAC techniques are straightforward for preventing the Hippo signaling in cancer therapy.