Hippo/YAP Pathway's Complex Regulation and Dysregulation in Cancer Synthesized for Therapeutic Targeting

The Hippo/YAP signaling pathway is a fundamental regulatory network crucial for maintaining organ size, tissue homeostasis, cell proliferation, and cell polarity. Its aberrant activation or suppression is a recognized contributor to the initiation and progression of numerous cancers, making it an attractive target for novel therapies. Despite promising preclinical results with Hippo/YAP-targeting agents, clinical translation has been limited, primarily due to an incomplete understanding of its intricate upstream regulators, downstream effectors, and complex pathway crosstalk.

This review systematically synthesized existing literature on the Hippo/YAP signaling pathway, analyzing its core components, regulatory mechanisms, and interactions with other signaling cascades. Researchers examined its dysregulation across various tumor types, including the involvement of microRNAs and lncRNAs in pathway modulation. The authors aimed to summarize current knowledge, identify challenges in clinical translation, and highlight emerging therapeutic strategies targeting Hippo/YAP to clarify complexities and reveal new therapeutic vulnerabilities.

The comprehensive review elucidated that aberrant Hippo/YAP signaling is a consistent driver of cancer initiation and progression, underscoring its critical roles in organ size, tissue homeostasis, cell proliferation, and cell polarity. It detailed the intricate upstream regulators and downstream effectors, emphasizing significant pathway crosstalk that complicates targeted interventions and contributes to context-dependent roles across different tumor types.

The synthesis revealed that while several agents targeting Hippo/YAP have demonstrated promise in preclinical models, their clinical translation is significantly hampered by an incomplete understanding of these complex regulatory networks. The authors highlighted the critical involvement of microRNAs and lncRNAs in modulating Hippo/YAP activity, presenting these as novel avenues for therapeutic exploration. Furthermore, the review cataloged emerging therapeutic strategies, acknowledging the urgent need for continued mechanistic investigation to overcome current translational barriers.