Hippo-YAP1 dysregulation as a central driver of therapeutic resistance in cancer: mechanisms and targeting therapeutic 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.