title: Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia.
abstract: Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step. We interrogated here especially the replication-independent transcription-coupled-NER ((TC)-NER) in prospective trial patients, primary CLL cultures, cell lines and mice. We screen selected (TC)-NER-targeting compounds as experimental (illudins) or clinically approved (trabectedin) drugs. They inflict transcription-stalling DNA lesions requiring TC-NER either for their removal (illudins) or for generation of lethal strand breaks (trabectedin). Genetically defined systems of NER deficiency confirmed their specificity. They selectively and efficiently induced cell death in CLL, irrespective of high-risk cytogenetics, IGHV status or clinical treatment history, including resistance. The substances induced ATM/p53-independent apoptosis and showed marked synergisms with fludarabine. Trabectedin additionally perturbed stromal-cell protection and showed encouraging antileukemic profiles even in aggressive and transforming murine CLL. This proof-of-principle study established (TC)-NER as a mechanism to be further exploited to resensitize CLL cells.
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: G
authors: G
authors: Lohmann
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: E
authors: E
authors: Vasyutina
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: J
authors: J
authors: Bloehdorn
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: N
authors: N
authors: Reinart
authors: Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany.
authors: J I
authors: JI
authors: Schneider
authors: Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany.
authors: V
authors: V
authors: Babu
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: G
authors: G
authors: Knittel
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: G
authors: G
authors: Crispatzu
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: P
authors: P
authors: Mayer
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: C
authors: C
authors: Prinz
authors: Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany.
authors: J K
authors: JK
authors: Muenzner
authors: Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany.
authors: B
authors: B
authors: Biersack
authors: Molecular Hematology Unit, ICGEB, Trieste, Italy.
authors: D G
authors: DG
authors: Efremov
authors: Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy.
authors: L
authors: L
authors: Chessa
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: C D
authors: CD
authors: Herling
authors: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors: S
authors: S
authors: Stilgenbauer
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: M
authors: M
authors: Hallek
authors: Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany.
authors: R
authors: R
authors: Schobert
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: H C
authors: HC
authors: Reinhardt
authors: Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany.
authors: B
authors: B
authors: Schumacher
authors: Laboratory of Lymphocyte Signaling and Oncoproteome, Department of Internal Medicine I, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.|Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: M
authors: M
authors: Herling
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D004260:DNA Repair / Q000235:genetics*; D004149:Dioxoles / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use; D000077606:Trabectedin; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D014740:Vidarabine; D000077606:Trabectedin; C024352:fludarabine