Basroparib inhibits YAP ‐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.