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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The Hippo signaling pathway controls genes vital for cell proliferation and survival.
• Its components are recognized as potential antitumor drug targets.
• Designing Hippo pathway inhibitors presents challenges due to network complexity and element redundancy.

Purpose of the Study:

• To review the current understanding of the Hippo signaling pathway.
• To explore strategies for designing pharmacological inhibitors of Hippo signaling.
• To discuss initial clinical trial outcomes for Hippo pathway modulators.

Main Methods:

• Review of existing literature on Hippo pathway structure and function.
• Analysis of microenvironment-induced extracellular cues.
• Evaluation of small molecule modulators for Hippo signaling inactivation.
• Assessment of PROTAC techniques and protein-protein interaction disruption.

Main Results:

• The Hippo pathway's kinases retain partners in a transcriptionally inactive state, making direct kinase inhibition counterproductive.
• Disrupting protein-protein interactions offers an alternative inhibition strategy.
• PROTAC (proteolysis-targeting chimera) techniques are emerging as viable alternatives.

Conclusions:

• Direct inhibition of Hippo pathway kinases is counterproductive due to their function.
• Alternative strategies, including protein-protein interaction disruption and PROTACs, are more effective for cancer therapy.
• These novel approaches hold promise for preventing Hippo signaling in cancer treatment.