PO.CL01.01 · 临床研究

一种肿瘤不可知的YAP/TAZ评分可独立于Hippo改变预测TEAD抑制剂敏感性

A tumor-agnostic YAP/TAZ score predicts TEAD inhibitor sensitivity independent of Hippo alterations

编号 1028 展板 22 时间 4/19 02:00–05:00 区域 Section 40 主讲 Michael Wegert-Verhoeven, BS;MD

分会场 Biomarkers Predictive of Therapeutic Benefit 1

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作者与单位 Authors & Affiliations

Michael Wegert-Verhoeven¹, Mathea Fransisca¹, Sylvia Martin¹, Attila Jady², Daniela Richter³, Malgorzata Oles⁴, Timon A. Blindauer⁵, Jan-Philipp Mallm⁶, Jasmina Paluncic², Claudia Dagostino², Olga Ermakova⁷, Annika Schneider⁸, Matthew The⁸, Annika Baude-Müller⁹, Katja Beck¹⁰, Maximilian Bullemer¹, Victor Didier Perez Meza¹¹, Vivek Venkataramani¹², Ralf C. Bargou¹², Heiko Becker¹³, Melanie Boerries¹⁴, Armin Tuchscherer¹⁵, DKFZ/NCT/DKTK MASTER consortium¹⁶, Martin Wermke¹⁷, Andreas Brunschweiger¹⁸, Mohammed Al-Saeedi¹⁹, Dirk Jäger²⁰, Olaf Witt²¹, Denis Schapiro⁵, Bernhard Küster²², Andreas Hartig²³, Michael Allgaeuer²⁴, Alexander Brobeil²⁵, Christoph E. Heilig¹⁰, Maria Veronica Teleanu¹⁰, Simon Kreutzfeldt¹⁰, Peter Horak¹⁰, Daniel Hübschmann²⁶, Wolfgang Hartmann²⁷, Marcel Trautmann²⁷, Ina Oehme²⁸, Claudia R. Ball²⁹, Stefan Fröhling³⁰, Stefan M. Pfister³¹, Hanno Glimm³², Sebastian M. Dieter³³

¹Section Translational Precision Oncology, Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Translational Functional Cancer Genomics, NCT Heidelberg and DKFZ, Heidelberg, Germany,²Department for Translational Medical Oncology, NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany,³Department for Translational Medical Oncology, NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden and Helmholtz-Zentrum Dresden-Rossendorf (HZDR); German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany,⁴Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), NCT Heidelberg and DKFZ, Heidelberg Germany, Heidelberg, Germany,⁵Institute for Computational Biomedicine, Faculty of Medicine, University Hospital Heidelberg, Heidelberg University; Translational Spatial Profiling Center (TSPC), Heidelberg; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany,⁶Single-cell Open Lab, DKFZ, Heidelberg, Center for Quantitative Analysis of Molecular and Cellular Biosystems (BioQuant), Heidelberg University, Heidelberg, Germany,⁷Division of Pediatric Neurooncology, DKFZ, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,⁸School of Life Sciences, Technical University of Munich, Freising, Germany,⁹Division of Translational Medical Oncology, DKFZ, Heidelberg, National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ, The University Hospital Heidelberg (UKHD), The Heidelberg Medical Faculty of the Heidelberg University, and The Thorax Clinic Heidelberg, Heidelberg, Germany,¹⁰Division of Translational Medical Oncology, DKFZ, Heidelberg, National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ, The University Hospital Heidelberg (UKHD), The Heidelberg Medical Faculty of the Heidelberg University, and The Thorax Clinic Heidelberg; DKTK, Core Center Heidelberg,, Heidelberg, Germany,¹¹Institute for Computational Biomedicine, Faculty of Medicine, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany,¹²Comprehensive Cancer Center Mainfranken, NCT WERA, University Hospital Würzburg, Würzburg, Germany,¹³Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany,¹⁴Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg; DKTK, Partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany,¹⁵Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital, Cologne, Heidelberg, Germany,¹⁶Molecularly Aided Stratification for Tumor Eradication Research Program, NCT Berlin, NCT Dresden, NCT Heidelberg, NCT SüdWest, NCT WERA, NCT West, DKFZ; DKTK sites: Berlin, Dresden, Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Heidelberg, München, Tübingen, One NCT, Germany,¹⁷TU Dresden, NCT/UCC Early Clinical Trial Unit and Medical Clinic and Poliklinik I, University of Technology Dresden (TUD), Dresden, Germany,¹⁸Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Am Hubland, Würzburg, Germany,¹⁹Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany,²⁰Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany,²¹Clinical Cooperation Unit Pediatric Oncology, DKFZ and DKTK, Hopp Children's Cancer Center Heidelberg (KiTZ); Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany,²²School of Life Sciences, Technical University of Munich, German Cancer Consortium (DKTK), partner site Munich a partnership between DKFZ and Technical University of Munich (TUM), Munich, Germany,²³Institute of Pathology, Carl Gustav Carus University Hospital, Dresden, Germany,²⁴Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany,²⁵Institute of Pathology, University Hospital Heidelberg, Tissue Bank of the NCT, Heidelberg, Heidelberg, Germany,²⁶Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), NCT Heidelberg and DKFZ; DKTK, Core Center Heidelberg, Heidelberg, Germany,²⁷West German Cancer Center, University Hospital Münster, Münster, Germany,²⁸Clinical Cooperation Unit Pediatric Oncology, NCT and DKFZ Heidelberg and DKTK Heidelberg, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany,²⁹Department for Translational Medical Oncology, NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden and Helmholtz-Zentrum Dresden-Rossendorf (HZDR); TUD Dresden University of Technology, Faculty of Biology, Dresden, Germany,³⁰Division of Translational Medical Oncology, DKFZ, Heidelberg, National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ, The University Hospital Heidelberg (UKHD), The Heidelberg Medical Faculty of the Heidelberg University, and The Thorax Clinic Heidelberg; DKTK, Core Center Heidelberg, Heidelberg, Germany,³¹Division of Pediatric Neurooncology, DKFZ, Heidelberg, Hopp Children's Cancer Center Heidelberg (KiTZ); Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany,³²Department for Translational Medical Oncology, NCT/UCC Dresden, Translational Functional Cancer Genomics, NCT Heidelberg and DKFZ; German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany,³³Section Translational Precision Oncology, Division of Translational Medical Oncology, NCT and DKFZ Heidelberg; Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany

摘要 Abstract

中文摘要

YAP和TAZ是Hippo通路效应因子，它们结合TEAD转录因子以驱动致癌程序。TEAD抑制剂（TEADi）的首次人体试验在既往治疗过的间皮瘤患者中显示出活性和耐受性，然而当前试验聚焦于间皮瘤和罕见的Hippo改变肿瘤，尽管YAP/TAZ在多种实体瘤中具有广泛的致癌作用。YAP/TAZ靶基因标签能否识别出具有高YAP/TAZ活性和潜在TEADi敏感性的、超出这些适应症之外的肿瘤，仍不明确。我们使用一个22基因标签，在来自INFORM和DKFZ/NCT/DKTK MASTER（MASTER）试验的2390例晚期儿童癌症以及3746例晚期罕见癌症或年轻成人（<51岁）癌症中分析了YAP/TAZ活性。以间皮瘤和YAP融合驱动的室管膜瘤为基准，揭示了各实体篮子中存在具有相当或更高YAP/TAZ活性、独立于Hippo改变的癌症亚群。为剖析肿瘤内在与基质的贡献，我们使用微阵列和Xenium平台对MASTER样本进行了空间转录组学分析（n=106个核心，来自代表>70种组织学亚型的89个肿瘤）。肿瘤细胞YAP/TAZ评分与整体（bulk）评分强相关（r=0.61），而成纤维细胞（r=0.23）和免疫细胞（r=0.35）的相关性较弱，表明整体评分很大程度上反映肿瘤细胞活性。我们重点报道了一例MET扩增癌的MASTER患者，其在MET抑制剂capmatinib治疗中的进展与YAP/TAZ评分的显著升高相吻合。在MET扩增的HS746T胃癌细胞中，遗传性YAP/TAZ激活降低了capmatinib敏感性，而这可被TEAD抑制部分逆转，支持一种此前未被认识的YAP/TAZ相关耐药机制。为评估YAP/TAZ标签的预测能力，用IAG933（Ω-环结合型TEADi）或VT107（TEAD自棕榈酰化抑制剂）处理了23个癌细胞系和30个患者来源的球体培养物（PDSC）。跨化合物和模型，与TEADi应答最强相关的基因表达富集于YAP/TAZ靶点，从而能够优化TEADi应答标签。这一优化后的标签与药物应答曲线下面积（AUC）值相关（IAG933：细胞系Pearson r=0.81，PDSC r=0.60；VT107：r=0.46和r=0.45）。值得注意的是，从INFORM/MASTER肿瘤衍生的优化标签可预测匹配PDSC中的TEADi应答（n=13；IAG933 r=0.70，VT107 r=0.72），IC50值低至30 nM。敏感的PDSC包括非典型畸胎样/横纹肌样瘤、结直肠癌和胰腺癌——它们均缺乏Hippo改变，且代表通常不被认为由YAP/TAZ驱动的实体。总之，这些数据为一项基于转录的分层临床试验提供了充分依据，该试验将在儿童和成人晚期癌症中评估TEAD抑制，而不论其Hippo改变状态。

查看英文原文 English abstract

YAP and TAZ are Hippo pathway effectors that bind TEAD transcription factors to drive oncogenic programs. First-in-human trials of TEAD inhibitors (TEADis) showed activity and tolerability in pretreated mesothelioma patients, yet current trials focus on mesotheliomas and rare Hippo-altered tumors, despite the broad oncogenic role of YAP/TAZ in various solid cancers. Whether YAP/TAZ target gene signatures can identify tumors with high YAP/TAZ activity and potential TEADi sensitivity beyond these indications remains unclear. We profiled YAP/TAZ activity using a 22-gene signature across 2390 advanced pediatric and 3746 advanced rare cancers or cancers from young adults (<51y) from the INFORM and DKFZ/NCT/DKTK MASTER (MASTER) trials. Benchmarking against mesothelioma and YAP fusion-driven ependymoma revealed subsets of cancers across entity baskets with equal or higher YAP/TAZ activity independent of Hippo alterations. To dissect tumor-intrinsic versus stromal contributions, we performed spatial transcriptomics on MASTER samples using microarrays and the Xenium platform (n=106 cores from 89 tumors representing >70 histological subtypes). Tumor-cell YAP/TAZ scores correlated strongly with bulk scores (r=0.61), whereas fibroblast (r=0.23) and immune-cell (r=0.35) correlations were weak, indicating that bulk scores largely reflect tumor-cell activity. We highlight a MASTER patient with MET-amplified carcinoma in whom progression on the MET inhibitor capmatinib coincided with a marked YAP/TAZ-score increase. In MET-amplified HS746T gastric cancer cells, genetic YAP/TAZ activation reduced capmatinib sensitivity, partially reversed by TEAD inhibition, supporting an unrecognized YAP/TAZ-linked resistance mechanism. To evaluate predictive capacity of the YAP/TAZ signature, 23 cancer cell lines and 30 patient-derived spheroid cultures (PDSCs) were treated with IAG933 (Ω-loop-binding TEADi) or VT107 (TEAD autopalmitoylation inhibitor). Across compounds and models, expression of genes most strongly associated with TEADi response were enriched for YAP/TAZ targets, enabling refinement of a TEADi response signature. This refined signature correlated with area-under-the-drug-response-curve (AUC) values (IAG933: Pearson r=0.81 for cell lines, r=0.60 for PDSCs; VT107: r=0.46 and r=0.45). Notably, the refined signature derived from INFORM/MASTER tumors predicted TEADi response in matched PDSCs (n=13; r=0.70 for IAG933, r=0.72 for VT107), with IC50 values as low as 30 nM. Sensitive PDSCs included atypical rhabdoid tumor, colorectal, and pancreatic carcinoma - all lacking Hippo alterations and representing entities not typically considered YAP/TAZ-driven. In summary, these data provide a strong rationale for a transcription-based stratified clinical trial evaluating TEAD inhibition across pediatric and adult advanced cancers irrespective of Hippo alterations.

利益披露 Disclosure

M. Wegert-Verhoeven, None.. M. Fransisca, None.. S. Martin, None.. A. Jady, None.. D. Richter, None.. M. Oles, None.. T. A. Blindauer, None.. J. Mallm, None.. J. Paluncic, None.. C. Dagostino, None.. O. Ermakova, None.. A. Schneider, None.. M. The, None.. A. Baude-Müller, None.. K. Beck, None.. M. Bullemer, None.. V. D. P. Meza, None.. V. Venkataramani, None.. R. C. Bargou, None.. H. Becker, None.. M. Boerries, None.. A. Tuchscherer, None.. D. MASTER consortium, None.. M. Wermke, None.. A. Brunschweiger, None.. M. Al-Saeedi, None.. D. Jäger, None.. O. Witt, None.. D. Schapiro, None.. B. Küster, None.. A. Hartig, None.. M. Allgaeuer, None.. A. Brobeil, None.. C. E. Heilig, None.. M. V. Teleanu, None.. S. Kreutzfeldt, None.. P. Horak, None.. D. Hübschmann, None.. W. Hartmann, None.. M. Trautmann, None.. I. Oehme, None.. C. R. Ball, None.. S. Fröhling, None.. S. M. Pfister, None.. H. Glimm, None.. S. M. Dieter, None.

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