An important step in the malfunctioning of the Hippo signalling pathway has been identified, opening a new door to the development of novel anti-cancer therapeutics.
Scientists from Hiroshima University and the University of California, San Diego have discovered a crucial step in the Hippo signalling pathway that governs cell division, proliferation and death, and whose malfunction contributes to the growth of tumours. Their findings suggest that the combination of a Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ)-targeting drug, and epidermal growth factor receptor (EGFR)-targeting therapy may help prevent cancer recurrence and progression.
In animal cells, the Hippo signalling pathway controls organ size by regulating cell division, proliferation, and death through a cascade of chemical reactions. The pathway is named after the Hpo or “hippo” kinase that works as a biological on/off switch by adding or removing phosphates and plays a critical role in many cellular processes including the cell cycle.
Since many cancers are the product of uncontrolled cell division and an aberration in the Hippo pathway can compromise the activity of YAP and TAZ, a pair of downstream targets that help regulate the transcription of genes involved in cell proliferation, this pathway has garnered significant attention in research and treatment development.
Previous research has shown that when the Hippo signalling pathway is active, YAP is inhibited and helps to control tumour suppression. In contrast, when the pathway is inactive, YAP becomes persistently active and promotes cell proliferation. However, the precise mechanism by which YAP/TAZ is activated is poorly understood. It is only known that the gene encoding EGFR, a protein that helps cells grow, is often over-expressed, especially in head and neck squamous cell carcinoma, and that EGFR is often mutated and activated in lung adenocarcinoma. Therefore, EGFR is commonly targeted by kinase inhibitor drugs or blocking antibodies for anti-cancer therapies. But the question of whether EGFR controls YAP/TAZ activation has remained unanswered.
“EGFR fails to reduce phosphorylation of YAP in some cellular systems, but inhibits the Hippo pathway to activate YAP in others,” said Toshinori Ando, the main researcher working on the study and Assistant Professor at the Center of Oral Clinical Examination at Hiroshima University Hospital (with a cross-appointment as a post-doctoral scientist in the University of California, San Diego). “If EGFR is being targeted by therapeutics, we really should know a bit more about why we’re doing this.”
In the current study, the researchers conducted a series of investigations of Hippo pathway mechanisms via comparisons of EGFR gene expression and the activation of YAP in a series of head and neck squamous cell carcinoma cells. They also examined cells that showed the highest expression of EGFR, analysed all cancer types, and performed a gene set enrichment analysis – a technique of identifying groups of genes that are over-represented within a large set and may be associated with certain diseases.
Based on their results, they concluded that EGFR activation promotes tyrosine phosphorylation of one of the core Hippo pathway components called MOB1. MOB1 is a gene that directs the activation of kinases LATS1 and LATS2, which modulate the function of the YAP/TAZ. The EGFR-promoted MOB1 tyrosine phosphorylation, followed by LATS1/2 inactivation leads to aberrant YAP/TAZ activation in many cancers that harbour EGFR alterations such as head and neck squamous cell carcinoma and lung adenocarcinoma.
“Emerging evidence have shown that YAP is overexpressed and contributes to cancer growth, poor prognosis, and acquired resistance to EGFR-targeted drugs in HNSCC and LUAC, although the mechanism of YAP re-activation is unclear,” added J. Silvio Gutkind, lead researcher of this project and Professor at the University of California, San Diego.
By identifying this EGFR-MOB1-YAP/TAZ signalling axis, the study has opened a new avenue for cancer therapy. They reported that a combination of therapies that target the EGFR and YAP/TAZ could prevent cancer cells from acquiring resistance that might have occurred if just one or the other therapies were used on their own. While a YAP/TAZ-targeting drug has yet to be approved for cancer treatment, the researchers believe one such drug is urgently needed to clarify the unknown mechanism of YAP re-activation. [APBN]
Source: Ando et al. (2021). EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1. Communications Biology, 4, 1237