The Hippo pathway is an internal signaling network that cells use to direct tissue growth and control organ size. It functions as a communication line within cells, interpreting signals from the cellular environment to regulate proliferation and cell death. When this pathway operates correctly, it maintains a healthy balance, ensuring tissues do not overgrow. A malfunction in this system can disrupt this balance, leading to the uncontrolled cell growth that is a defining characteristic of cancer.
The Hippo Pathway’s Role in Cell Regulation
The Hippo pathway functions like a cellular brake system, governing cell growth and division. Its default state is “on,” restraining growth to maintain tissue size. The core of this mechanism is a cascade of proteins, primarily the kinases MST1/2 and LATS1/2. When active, MST1/2 phosphorylates and activates LATS1/2.
This activation targets the primary drivers of cell proliferation, two related proteins named YAP and TAZ. Activated LATS1/2 kinases phosphorylate YAP and TAZ, tagging them for neutralization. This tag confines YAP and TAZ to the cytoplasm, outside the nucleus. Once in the cytoplasm, they are marked for degradation, preventing them from influencing gene activity.
If the kinases are the “brake,” then YAP and TAZ are the “gas pedal” for cell growth. These proteins are transcriptional co-activators, partnering with other proteins in the nucleus to turn on genes. When the Hippo pathway’s brake is disengaged, for instance, for tissue repair, the kinase cascade becomes inactive. Without restraining phosphorylation from LATS1/2, YAP and TAZ are free to travel into the cell’s nucleus.
Inside the nucleus, YAP and TAZ bind to transcription factors, most notably the TEAD family of proteins. This partnership forms a complex that switches on genes that promote cell division and inhibit programmed cell death, or apoptosis. This “brake off” state is a normal part of tissue maintenance, allowing for controlled growth when needed. The pathway’s ability to switch between these states maintains tissue balance.
How a Faulty Hippo Pathway Drives Cancer
When the Hippo pathway’s brake system fails, it can lead to cancer development. This failure occurs when braking components are broken, often from mutations in the genes that encode the MST1/2 or LATS1/2 kinases. These mutations can render the tumor-suppressing proteins non-functional. Similarly, mutations affecting upstream regulators like NF2 can prevent the activation of the kinase cascade.
This dysregulation is a documented driver in several specific types of human cancers. In hepatocellular carcinoma (the most common liver cancer), YAP is frequently overactive and is a factor in tumor development. High levels of YAP in these tumors correlate with a poorer prognosis. The pathway’s failure is also a factor in malignant mesothelioma, an aggressive cancer where mutations in the regulator NF2 are found in approximately 20-40% of cases.
In certain types of non-small cell lung cancer (NSCLC), the hyperactivation of YAP sustains cancer cell invasion and metastasis. This can be caused by various factors, including the silencing of other tumor-suppressing genes that regulate the Hippo pathway. The consistent finding is that a broken Hippo pathway leads to unchecked YAP/TAZ activity, transforming them into potent oncogenic drivers.
Developing Cancer Therapies by Targeting the Hippo Pathway
The Hippo pathway’s role in driving tumor growth has made it a focus for the development of new cancer therapies. Research is progressing along several distinct strategic lines, each aiming to correct the pathway’s malfunction. These approaches are largely in preclinical or early-stage clinical development.
One strategy involves the direct inhibition of the pathway’s growth activators, YAP and TAZ. The goal is to develop small-molecule drugs that can block these proteins, preventing them from entering the nucleus or from binding to their TEAD partners. This approach is challenging because YAP and TAZ lack the typical pockets or active sites that are targeted by conventional drugs. Despite this difficulty, researchers are actively screening for compounds that can disrupt the interaction between YAP/TAZ and TEAD proteins.
An alternative approach seeks to reactivate the pathway’s natural braking system. This strategy aims to find molecules that can turn the MST and LATS kinases back on. Restoring the function of these kinases would re-establish the phosphorylation of YAP and TAZ, trapping them in the cytoplasm and stopping the pro-cancer signaling.
A third therapeutic avenue focuses on the downstream partners that YAP and TAZ require to function. Since the YAP/TAZ-TEAD protein complex is what ultimately activates cancer-promoting genes, blocking this interaction is a primary goal. Several inhibitors have been developed that specifically target the TEAD family of transcription factors, preventing them from binding to YAP and TAZ. These therapies can halt the signal for uncontrolled growth, even in cancers where the upstream Hippo kinases are non-functional.