PO.ET03.02 · 实验与分子治疗

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

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

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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