Data from: 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 tumours harbouring 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 signalling—attenuates YAP‑driven oncogenic
programmes by stabilising 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 sensitised YAP‑overexpressing,
KRAS‑mutant CRC cell lines to MEK inhibition by disrupting the AMOT–YAP
axis. 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 tumour 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.

Yes相关蛋白（Yes-associated protein，YAP）是关键的致癌效应因子，亦是公认的抗癌治疗耐药驱动因素，尤其在携带KRAS突变的肿瘤中。尽管YAP具有明确的临床相关性，但直接靶向抑制其活性的药物开发工作始终进展有限。本研究证实，巴罗帕利（basroparib）——一种可抑制Wnt信号通路的选择性端锚聚合酶（tankyrase，TNKS）抑制剂——通过稳定血管动蛋白（angiomotin，AMOT，YAP的内源性负调控因子），削弱YAP介导的致癌程序。在结直肠癌（colorectal cancer，CRC）细胞中，巴罗帕利可提升AMOT的蛋白丰度，促进AMOT-YAP复合物的形成，并迫使YAP发生细胞质滞留，从而抑制YAP依赖的基因转录。巴罗帕利可通过破坏AMOT-YAP信号轴，优先使过表达YAP的KRAS突变CRC细胞系对MEK抑制产生敏感性。在YAP活性升高介导耐药逃逸的MEK抑制剂耐药CRC模型中，巴罗帕利可在体外及体内均恢复肿瘤对药物的敏感性。该化合物还可在其他YAP激活型肿瘤中增强MEK抑制剂的疗效，而在YAP非激活型模型中仅产生极微弱的干预效果。综上，本研究结果证实，巴罗帕利（目前正处于I期临床试验阶段，临床试验编号NCT04505839）可作为兼具Wnt-YAP双通路阻断作用的潜在治疗药物，用于克服YAP驱动型癌症的治疗耐药性。