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

被引：8

作者：

Lohmann, G. ^{[1
,2
]}

Vasyutina, E. ^{[1
,2
]}

Bloehdorn, J. ^{[3
]}

Reinart, N. ^{[1
,2
]}

Schneider, J. I. ^{[2
,4
]}

Babu, V. ^{[2
,4
]}

Knittel, G. ^{[1
,2
]}

Crispatzu, G. ^{[1
,2
]}

Mayer, P. ^{[1
,2
]}

Prinz, C. ^{[1
,2
]}

Muenzner, J. K. ^{[5
]}

Biersack, B. ^{[5
]}

Efremov, D. G. ^{[6
]}

Chessa, L. ^{[7
]}

Herling, C. D. ^{[1
,2
]}

Stilgenbauer, S. ^{[3
]}

Hallek, M. ^{[1
,2
]}

Schobert, R. ^{[5
]}

Reinhardt, H. C. ^{[1
,2
]}

Schumacher, B. ^{[2
,4
]}

Herling, M. ^{[1
,2
]}

机构：

[1] Univ Cologne, Ctr Integrated Oncol CIO Koln Bonn, Dept Internal Med 1, Lab Lymphocyte Signaling & Oncoproteome, Cologne, Germany

[2] Univ Cologne, Excellence Cluster Cellular Stress Response & Agi, Cologne, Germany

[3] Ulm Univ, Dept Internal Med 3, Ulm, Germany

[4] Univ Cologne, Med Fac, Inst Genome Stabil Ageing & Dis, Cologne, Germany

[5] Univ Bayreuth, Organ Chem Lab, Bayreuth, Germany

[6] ICGEB, Mol Hematol Unit, Trieste, Italy

[7] Univ Roma La Sapienza, Dept Clin & Mol Med, Rome, Italy

来源：

LEUKEMIA | 2017年 / 31卷 / 05期

关键词：

FLUDARABINE-MEDIATED INHIBITION; DNA-REPAIR; ANTITUMOR-ACTIVITY; TRANSGENIC MOUSE; TRABECTEDIN; IROFULVEN; CANCER; CELLS; EXPRESSION; APOPTOSIS;

D O I：

10.1038/leu.2016.294

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1177 / 1186

页数：10

共 54 条

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