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Mechanisms of resistance

Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia

Leukemia volume 31, pages 1177–1186 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by the German Research Foundation (DFG KFO-286) to MaHe (HE3552/3-2), BS, Mi Ha, HCR and CDH (HE7828/1-2). A Max-Eder Excellence Award by the German Cancer Aid (to MaHe), the CLL Global Research Foundation (to MaHe), the German Jose-Carreras foundation (to MaHe, DJCLS R 12/08) and the local CECAD initiative (to MaHe and BS) further supported this work. Trabectedin was provided by PhamaMar (Madrid, Spain); bendamustine by Mundipharma (Limburg, Germany). A Eggle (Salzburg, Austria) provided C57BL/6 Eμ-TCL1 founders. We thank N Riet for help with animal work.

Author contributions

GL designed, performed, analyzed the experiments and wrote the manuscript. EV analyzed statistical data on the CLL8 trial data set and wrote the manuscript. JB performed gene expression profiling and statistical data analysis on the CLL8 trial data set. PM, NR, CP, JS, VB and CDH performed experiments and analyzed data. DGE, GK and HCR provided mice. LC provided A-T cell lines. RS and BB designed/supervised compound chemistry. MiHa and SS provided access to trial samples and clinical data. MaHe and BS conceptualized the study, designed experiments, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine I, Laboratory of Lymphocyte Signaling and Oncoproteome, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany

    G Lohmann, E Vasyutina, N Reinart, G Knittel, G Crispatzu, P Mayer, C Prinz, C D Herling, M Hallek, H C Reinhardt & M Herling

  2. Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    G Lohmann, E Vasyutina, N Reinart, J I Schneider, V Babu, G Knittel, G Crispatzu, P Mayer, C Prinz, C D Herling, M Hallek, H C Reinhardt, B Schumacher & M Herling

  3. Department of Internal Medicine III, Ulm University, Ulm, Germany

    J Bloehdorn & S Stilgenbauer

  4. Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany

    J I Schneider, V Babu & B Schumacher

  5. Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany

    J K Muenzner, B Biersack & R Schobert

  6. Molecular Hematology Unit, ICGEB, Trieste, Italy

    D G Efremov

  7. Department of Clinical and Molecular Medicine, University La Sapienza, Roma, Italy

    L Chessa

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  1. G Lohmann
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  2. E Vasyutina
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  10. C Prinz
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Correspondence to M Herling.

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Lohmann, G., Vasyutina, E., Bloehdorn, J. et al. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia 31, 1177–1186 (2017). https://doi.org/10.1038/leu.2016.294

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