Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors
Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors
Abstract PARP inhibitors (PARPi) have become a new line of therapy for Homologous Recombination (HR)-deficient cancers. However, resistance to PARPi has emerged as a major clinical problem. DNA polymerase theta (POLθ) is synthetic lethal with HR and a druggable target in HR-deficient cancers. Here, we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. BRCA-deficient tumor cells and those with acquired PARPi resistance are sensitive to NVB in vitro and in vivo. Increased POLθ expression levels predict NVB sensitivity. The mechanism of NVB-mediated cell death in PARPi resistant cells is the accumulation of toxic RAD51 foci, which also provides a pharmacodynamic biomarker for NVB response. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. One Sentence SummaryWe identified Novobiocin as a specific POLθ inhibitor that selectively kills na?ve and PARPi resistance HR-deficient tumors in vitro and in vivo.
Pantelidou Constantia、Davis Rachel E.、Syed Aleem、D?ˉAndrea Alan D.、Li Adam、Shapiro Geoffrey I.、Farkkila Anniina、Gelot Camille、Y¨1cel Hatice、Ceccaldi Raphael、Blagg Brian S. J.、Tainer John A.、Kochupurakkal Bose、Zhou Jia
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical SchoolDepartment of Chemistry and Biochemistry, University of Notre DameDepartments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Center for DNA Damage and Repair, Dana-Farber Cancer InstituteDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School||Center for DNA Damage and Repair, Dana-Farber Cancer InstituteDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolInserm U830, PSL Research University, Institut CurieInserm U830, PSL Research University, Institut CurieInserm U830, PSL Research University, Institut CurieDepartment of Chemistry and Biochemistry, University of Notre DameDepartments of Cancer Biology and of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School
肿瘤学基础医学药学
NovobiocinPolymerase theta (POLθ)Homologous RecombinationPARP inhibitor resistance
Pantelidou Constantia,Davis Rachel E.,Syed Aleem,D?ˉAndrea Alan D.,Li Adam,Shapiro Geoffrey I.,Farkkila Anniina,Gelot Camille,Y¨1cel Hatice,Ceccaldi Raphael,Blagg Brian S. J.,Tainer John A.,Kochupurakkal Bose,Zhou Jia.Polymerase Theta Inhibition Kills Homologous Recombination Deficient Tumors[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2020.05.23.111658.点此复制
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