Basroparib inhibits <scp>YAP</scp> ‐driven cancers by stabilizing angiomotin

Yes-associated protein (YAP) is a key oncogenic effector and a well-established driver of resistance to anticancer therapies, especially in tumors harboring KRAS mutations. Although YAP is clinically relevant, drug-development efforts that directly inhibit its activity have been limited. Here, we show that basroparib-a selective tankyrase (TNKS) inhibitor that suppresses Wnt signaling-attenuates YAP-driven oncogenic programs by stabilizing angiomotin (AMOT), an endogenous negative regulator of YAP. In colorectal cancer (CRC) cells, basroparib increased AMOT protein abundance, promoted AMOT-YAP complex formation, and enforced cytoplasmic sequestration of YAP, thereby dampening YAP-dependent transcription. Basroparib preferentially sensitized YAP-overexpressing, KRAS-mutant CRC cell lines to MEK inhibition by inhibiting YAP signaling. In MEK inhibitor-resistant CRC models, in which elevated YAP activity mediates escape, basroparib restored drug sensitivity both in vitro and in vivo. The compound also enhanced MEK inhibitor efficacy in other YAP-active tumor types, while exerting minimal effects in YAP-inactive models. Taken together, these results identify basroparib-now progressing through clinical development (Phase I, NCT04505839)-as a promising agent for dual Wnt-YAP pathway blockade and for overcoming therapeutic resistance in YAP-driven cancers.