Nucleotide Excision Repair as a Targetable Vulnerability in Leukemia .Gregor Lohmann, Björn Schumacher, and Marco Herling .
... In systems of syngeneic transfers of leukemic splenocytes from Eμ-TCL1 initi-ated strains, their fludarabine-refractory subclones, and their engineered TP53-deficient variants, trabectedin was active at well-tolerated dosages. It delayed the outgrowth of the engrafted leukemic clone and prolonged the survival of animals.
In conclusion, because of the positive efficacy/toxicity profiles of our ‘TC-NER-active’ agents, we suggest the implementation of targeting of (TC)-NER as a salvage strategy in high-risk and refractory CLL patients or those in Richter’s transformation. As a pilot substance the well-known trabectedin appears attractive, particularly given its multi-effect profile that even goes beyond targeting NER-coupled DNA damage. [7] Its modulatory impact on the local microenvironment, particularly targeting the immunosuppressive and pro-angiogenic effects of polarized tumor-associated mac-rophages [8], is appealing with respect to ongoing efforts to convert the milieu of CLL towards a more immunogenic state.
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Scheme of postulated synergistic mechanisms of (TC)-NER-targeting
a “normal scenario”: Transcription-coupled nucleotide excision repair (TC-NER) specific DNA lesions are processed by the protective NER machinery mostly re-sulting in adequate DNA repair and cell survival. b “scenario of ‘TC-NER-active’ compounds in synergy with fludarabine in leuke-mia”: ‘TC-NER-active‘ compounds (illudinM, ferrocen-IM or trabectedin) induce enhanced rates of TC-NER specific lesions, while nucleotide excision repair mechanisms are simultaneously blocked by trabectedin. Fludarabine poisons the final gap-filling step of the NER cascade. The ‘TC-NER-active’ agents syn-ergistically cooperate with fludarabine. This induces mainly ATM/p53 independ-ent programmed cell death and can overcome therapeutic resistance.