What question did this study set out to answer?

To investigate how TNKS inhibition affects YAP signaling and overcomes therapy resistance in solid tumors.

April 5, 2026

Abstract 7118: TNKS inhibition rewires AMOT-YAP signaling to overcome YAP-driven therapy resistance in solid tumors

Key Points

To investigate how TNKS inhibition affects YAP signaling and overcomes therapy resistance in solid tumors.
Utilized YAP-high colorectal cancer models to assess TNKS inhibition effects.
Measured AMOT levels and YAP localization post-TNKS inhibition.
Evaluated therapeutic sensitivity to MEK inhibitors after TNKS intervention.
Conducted in vitro and in vivo experiments across various solid tumor models.
TNKS inhibition increased AMOT levels and enhanced AMOT-YAP complex formation.
Restrained YAP nuclear localization, reducing YAP transcriptional activity.
KRAS-mutant CRC cells became sensitive to MEK inhibitors following TNKS inhibition.
Combinatorial enhancement of sensitivity was observed across multiple YAP-activated tumor types.

Abstract

Abstract 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. Citation Format: Jae Sung Kim, Young-Ju Kwon, Dong Young Kim, Yuna Kim. TNKS inhibition rewires AMOT-YAP signaling to overcome YAP-driven therapy resistance in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7118.

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