PO.ET02.12 · 实验与分子治疗
IAG933抑制TEAD作为胆管癌的一种新型治疗策略
TEAD inhibition by IAG933 as a novel therapeutic strategy for cholangiocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胆管癌（CCA）是一种侵袭性的肝胆恶性肿瘤，具有显著的分子异质性、有限的全身治疗选择和不良预后。化疗耐药和KRAS突变仍是主要的治疗挑战。Hippo通路的失调，尤其是YAP/TAZ过度激活，驱动CCA进展和耐药。TEAD作为YAP/TAZ必需的转录伙伴，代表了一个有前景的靶点。IAG933是一种新型口服泛TEAD抑制剂，旨在破坏YAP/TAZ-TEAD相互作用。RMC-6236，一种泛KRAS抑制剂，也已受到关注。联合抑制TEAD和KRAS可能克服耐药并提高CCA的疗效。
方法：我们在人（HuCCT1、RBE）和鼠（SB1、FAC）CCA细胞系中评估IAG933。细胞用IAG933单独处理或与GemCis或RMC-6236联合处理。使用细胞活力检测确定IC50值并计算联合指数（CI）。通过荧光素酶报告基因和YAP/TAZ靶基因（CTGF、CYR61、NUAK2）的qRT-PCR评估TEAD活性。通过RNA测序分析转录组改变。在同基因原位模型和患者来源异种移植（PDX）模型中评估体内疗效。
结果：IAG933抑制TEAD依赖性转录（IC50 ≈ 500 nM）并下调YAP/TAZ靶基因。与GemCis或RMC-6236联用在所有CCA细胞系中产生协同效应（CI < 1）。转录组分析揭示了氧化应激反应通路的激活，尤其是SOD2上调。MitoSOX染色证实处理后线粒体ROS增加。在体内，IAG933单药抑制肿瘤生长的效果与GemCis相似。双重抑制TEAD和KRAS在KRAS突变型PDX模型中实现了显著的肿瘤消退，并在停药后显著延迟了肿瘤再生长。
结论：IAG933有效抑制YAP/TAZ-TEAD信号并抑制CCA生长。虽然与GemCis联用由于强大的单药疗效而显示出有限的额外获益，但与RMC-6236的协同作用产生了持久的抗肿瘤效应，尤其在停药观察研究中，延迟了KRAS突变型模型中的再生长。这些发现突显了IAG933作为靶向Hippo-TEAD通路的有前景的治疗候选药物，在KRAS突变型CCA中具有潜在获益。
查看英文原文 English abstract
Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with marked molecular heterogeneity, limited systemic treatment options, and poor prognosis. Chemoresistance and KRAS mutations remain major therapeutic challenges. Dysregulation of the Hippo pathway, particularly YAP/TAZ hyperactivation, drives CCA progression and resistance. TEAD, the essential transcriptional partner of YAP/TAZ, represents a promising target. IAG933 is a novel oral pan-TEAD inhibitor designed to disrupt YAP/TAZ-TEAD interactions. RMC-6236, a pan-KRAS inhibitor, has also gained attention. Combined TEAD and KRAS inhibition may overcome resistance and improve efficacy in CCA.
Methods: We evaluated IAG933 in human (HuCCT1, RBE) and murine (SB1, FAC) CCA cell lines. Cells were treated with IAG933 alone or in combination with GemCis or RMC-6236. Cell viability assays were used to determine IC₅₀ values and calculate combination indexes (CI). TEAD activity was assessed by luciferase reporter and qRT-PCR of YAP/TAZ target genes (CTGF, CYR61, NUAK2). Transcriptomic alterations were analyzed by RNA sequencing. In vivo efficacy was evaluated in syngeneic orthotopic and patient-derived xenograft (PDX) models.
Results: IAG933 suppressed TEAD-dependent transcription (IC₅₀ ≈ 500 nM) and downregulated YAP/TAZ target genes. Combination with GemCis or RMC-6236 produced synergistic effects (CI < 1) in all CCA lines. Transcriptomic analysis revealed activation of oxidative stress response pathways, particularly SOD2 upregulation. MitoSOX staining confirmed increased mitochondrial ROS after treatment. In vivo, IAG933 monotherapy suppressed tumor growth similarly to GemCis. Dual TEAD and KRAS inhibition achieved marked tumor regression and significantly delayed tumor regrowth after treatment cessation in KRAS-mutant PDX models.
Conclusion: IAG933 effectively suppresses YAP/TAZ-TEAD signaling and inhibits CCA growth. While the combination with GemCis showed limited additional benefit due to strong single-agent efficacy, synergy with RMC-6236 produced durable antitumor effects, particularly in run-out studies, delaying regrowth in KRAS-mutant models. These findings highlight IAG933 as a promising therapeutic candidate targeting the Hippo-TEAD pathway, with potential benefit in KRAS-mutant CCA.
利益披露 Disclosure
H. Nishi, None..
E. Jessen, None..
D. M. Carlson, None..
A. M. Abdelrahman, None..
E. H. Ozmert, None..
J. Fincatto Safi, None..
B. A. Wilbanks, None..
S. K. Yee, None..
J. W. Sample, None..
N. W. Werneburg, None..
R. L. Smoot, None.