Aug 2026· Critical reviews in oncology/hematology· pp.
105557
· 0 citations· 146 references
Medicine
TL;DR
A review summarizes the close link between Hippo-YAP1 dysregulation and drug resistance, and highlights intervention strategies with the potential to serve as novel treatment strategies.
Abstract
Persistent dysregulation of the Hippo-YAP1 signaling pathway is closely associated with tumor progression and therapeutic resistance, rendering it an exceptionally compelling yet complex target for intervention. To elucidate the potential of harnessing this pathway for cancer therapy, this review systematically integrates mechanistic and translational evidence across three interrelated dimensions. First, we outline the context-dependent roles of Hippo-YAP1 signaling in tumorigenesis, progression, and metastasis, highlighting how pathway activation or inhibition differentially impacts cell proliferation, metabolic reprogramming, epithelial-mesenchymal transition, and metastatic dissemination. Second, the current therapeutic strategies targeting the Hippo pathway are summarized, emphasizing direct inhibition of the YAP/TAZ-TEAD transcriptional complex and pharmacological modulation of upstream druggable regulators. Finally, we dissect how aberrant Hippo-YAP1 activation drives resistance to chemotherapy, radiotherapy, targeted therapies, and immunotherapy across multiple levels. Building upon these findings, we discuss combinatorial therapeutic approaches targeting YAP/TEAD and their specific partner pathways, while outlining molecular stratification strategies based on Hippo-YAP1 activation status and microenvironmental context. In summary, this review summarizes the close link between Hippo-YAP1 dysregulation and drug resistance, and highlights intervention strategies with the potential to serve as novel treatment strategies.
As the core transcriptional co-activators of the Hippo signaling pathway, YAP and TAZ play essential roles in maintaining tissue homeostasis and in tumorigenesis. Their aberrant activation is frequently observed in human malignancies, and accumulating evidence has identified them as crucial drivers of tumor initiation and progression. YAP/TAZ have been recently recognized as key regulators of cellular metabolic reprogramming, a hallmark of cancer that fuels tumor cell proliferation by rewiring glucose, lipid, amino acid, and nucleotide metabolism. Conversely, the activity of YAP/TAZ is modulated by metabolites such as glucose and lipids, establishing a complex bidirectional regulatory circuit. Therefore, deciphering this intricate crosstalk is of great importance for cancer therapy and drug discovery. In this review, we systematically clarify the interplay between YAP/TAZ and metabolic reprogramming in cancer, delineate the core molecular networks through which YAP/TAZ govern each metabolic pathway, and summarize the current pharmacological inhibitors targeting YAP/TAZ-regulated metabolic networks. Collectively, these findings pave the way for therapeutic approaches targeting YAP/TAZ-driven metabolic vulnerabilities in cancer.
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