PO.CL01.01 · 临床研究

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

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

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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