PO.ET03.02 · 实验与分子治疗

动态拷贝数变化和染色体外DNA的从头生成调控治疗耐药

Dynamic copy number changes and de novo generation of extrachromosomal DNA modulate therapy resistance

编号 1803 展板 23 时间 4/20 09:00–12:00 区域 Section 16 主讲 Martin Sprick, PhD

分会场 Mechanisms of Drug Resistance 2

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作者与单位 Authors & Affiliations

Tim Vorberg¹, Manuel Reitberger², Bernardo Rodriguez Martin³, Maja Starostecka⁴, Dominique Schulz², Arlou K. Angeles⁵, Kate I. Glennon⁶, Tasneem Cheytan², Roberto Würth⁷, Vera Thiel⁸, Paul Schwerd-Kleine², Verena Thewes⁹, Laura Michel¹⁰, Ewgenija Gutjahr¹¹, Simon J. Ogrodnik⁶, Heike Conrad¹², Steffi O. Mehlhorn², Vanessa Vogel², Corinna Klein², Albrecht Stenzinger¹³, Peter Lichter¹⁴, Andreas Schneeweiss¹⁵, Martin Granzow¹⁶, Marc Zapatka¹⁷, Anna Jauch¹⁶, Holger Sültmann¹⁸, Jan Korbel⁴, Andreas Trumpp¹⁹, Martin R. Sprick²

¹DKFZ German Cancer Research Center, Heidelberg, Germany,²German Cancer Research Center/HI-STEM, Heidelberg, Germany,³3Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany,⁴Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany,⁵4Division of Cancer Genome Research, German Cancer Research Center, Heidelberg, Germany,⁶Division of Cancer Genome Research, German Cancer Research Center, Heidelberg, Germany,⁷HI-STEM gGmbH, Heidelberg, Germany,⁸DKFZ German Cancer Research Center/HI-STEM, Heidelberg, Germany,⁹Gynecologic Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany,¹⁰National Center for Tumor Diseases (NCT), University of Heidelberg, Heideberg, Germany,¹¹Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany,¹²Institute of Pathology, Heidelberg University Hospital (UKHD), Heidelberg, Germany,¹³Heidelberg University Hospital (UKHD), Heidelberg, Germany,¹⁴6Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany,¹⁵Gynecologic Oncology,, National Center for Tumor Diseases (NCT), Heidelberg, Germany,¹⁶Institute of Human Genetics, University Heidelberg,, Heidelberg, Germany,¹⁷Computational Cancer Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany,¹⁸Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany,¹⁹German Cancer Research Center, Heidelberg, Germany

摘要 Abstract

中文摘要

染色体外DNA（ecDNA）日益被认为是细胞可塑性的驱动因素，然而其在胰腺导管腺癌（PDAC）治疗适应中的作用仍未得到充分界定。在患者来源的PDAC模型中，我们鉴定出染色体外ABCB1扩增是对paclitaxel和KRAS抑制剂耐药的一种机制，并表明ABCB1拷贝数会随选择压力动态调整。值得注意的是，paclitaxel耐药细胞仍处于快速从头生成ecDNA的预备状态：通过单细胞克隆消除预先存在的ABCB1 ecDNA后，新的、结构上不同的ABCB1 ecDNA迅速出现，表明治疗诱导的分子变化使这些细胞处于形成ecDNA的预备状态。在转移性乳腺癌中，同样观察到紫杉烷相关的ABCB1扩增，并可在游离DNA（cfDNA）中追踪，凸显了超越PDAC的临床相关性。最后，gemcitabine联合治疗抑制了ABCB1 ecDNA的生成，提示对抗ecDNA介导耐药的潜在策略。总之，这些发现证明动态ecDNA调控和可诱导的ecDNA生物发生使快速、可逆的耐药成为可能，为ecDNA靶向联合治疗和纵向监测提供了理论依据。

查看英文原文 English abstract

Extrachromosomal DNA (ecDNA) is increasingly recognized as a driver of cellular plasticity, yet its role in therapy adaptation in pancreatic ductal adenocarcinoma (PDAC) remains poorly defined. In patient-derived PDAC models, we identify extrachromosomal ABCB1 amplification as a mechanism of resistance to paclitaxel and KRAS inhibitors and show that ABCB1 copy number dynamically adjusts to selective pressure. Notably, paclitaxel-resistant cells remain primed for rapid de novo ecDNA generation: after eliminating pre-existing ABCB1 ecDNA through single-cell cloning, new and structurally distinct ABCB1 ecDNA rapidly emerges, indicating treatment-induced molecular changes that prime these cells for ecDNA formation. In metastatic breast cancer, taxane-associated ABCB1 amplification is likewise observed and can be tracked in cell-free DNA (cfDNA), underscoring clinical relevance beyond PDAC. Finally, gemcitabine co-treatment suppresses ABCB1 ecDNA generation, suggesting potential strategies to counteract ecDNA-mediated resistance. Together, these findings demonstrate that dynamic ecDNA modulation and inducible ecDNA biogenesis enable rapid, reversible drug resistance, providing a rationale for ecDNA-targeted combination therapies and longitudinal monitoring.

利益披露 Disclosure

M. Reitberger, None.. B. Rodriguez Martin, None.. M. Starostecka, None.. D. Schulz, None.. A. K. Angeles, None.. K. I. Glennon, None.. T. Cheytan, None.. V. Thiel, None. P. Schwerd-Kleine, Novartis Employment. V. Thewes, None.. S. J. Ogrodnik, None.. H. Conrad, None.. S. O. Mehlhorn, None.. V. Vogel, None.. C. Klein, None.. A. Schneeweiss, None.. M. Granzow, None.. A. Jauch, None.. J. Korbel, None.. M. R. Sprick, None.

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