TNKS抑制重塑AMOT-YAP信号以克服实体瘤中YAP驱动的治疗耐药

Therapy-resistant tumors frequently rely on hyperactivated YAP signaling, particularly in KRAS-mutant contexts, where YAP serves as a major bypass survival pathway. Because direct pharmacologic inhibition of YAP remains challenging, strategies that modulate its upstream regulatory networks are required. Here, we demonstrate that tankyrase (TNKS) inhibition attenuates YAP oncogenic output by stabilizing angiomotin (AMOT), a core scaffold protein that promotes YAP cytoplasmic sequestration. In YAP-high colorectal cancer (CRC) models, TNKS inhibition increased AMOT abundance, strengthened AMOT-YAP complex formation, and restricted YAP nuclear localization, leading to a global reduction in YAP-dependent transcriptional activity. This reprogramming of YAP signaling sensitized KRAS-mutant CRC cells to MEK inhibition, indicating that the TNKS-AMOT axis directly intersects adaptive resistance mechanisms. In CRC models with established MEK inhibitor resistance driven by YAP reactivation, TNKS inhibition restored therapeutic sensitivity in vitro and in vivo. Similar combinatorial enhancement was observed across additional YAP-activated solid tumors, including pancreatic, lung, and breast cancers, while YAP-inactive tumors showed minimal response, highlighting pathway specificity. Together, these findings support TNKS inhibition as a mechanistically grounded approach to constrain YAP-driven oncogenic signaling through AMOT stabilization, offering a promising therapeutic strategy to overcome YAP-mediated resistance and improve targeted or radiation-based treatment responses in YAP-dependent cancers.