2. Academic Validation
  3. SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters

  • Cancers (Basel). 2023 Jun 3;15(11):3043. doi: 10.3390/cancers15113043.
Elisabeth Groß 1,  Ralf-Axel Hilger 2,  Franziska Lea Schümann 1,  Marcus Bauer 3,  Alyssa Bouska 4,  Christian Rohde 5,  Edith Willscher 1,  Jana Lützkendorf 1,  Lutz Peter Müller 1,  Bayram Edemir 1,  Thomas Mueller 1,  Marco Herling 6,  Mascha Binder 1,  Claudia Wickenhauser 3,  Javeed Iqbal 4,  Guido Posern 7,  Thomas Weber 1
Affiliations

Affiliations

  • 1 Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany.
  • 2 West German Cancer Center, University Hospital Essen, 45147 Essen, Germany.
  • 3 Institute of Pathology, Martin-Luther-University Halle-Wittenberg, 06112 Halle (Saale), Germany.
  • 4 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 5 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 6 Department of Hematology, Cell Therapy, Hemostaseology, University of Leipzig, 04103 Leipzig, Germany.
  • 7 Institute for Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, 06114 Halle (Saale), Germany.
PMID: 37297005 DOI: 10.3390/cancers15113043
Abstract

T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. EZH2 is overexpressed in several tumor entities including T-cell neoplasms leading to epigenetic and consecutive oncogenic dysregulation. Thus, pharmacological EZH2 inhibition is a promising target and its clinical evaluation in T-cell lymphomas shows favorable results. We have investigated EZH2 expression in two cohorts of T-cell lymphomas by mRNA-profiling and immunohistochemistry, both revealing overexpression to have a negative impact on patients' prognosis. Furthermore, we have evaluated EZH2 inhibition in a panel of leukemia and lymphoma cell lines with a focus on T-cell lymphomas characterized for canonical EZH2 signaling components. The cell lines were treated with the inhibitors GSK126 or EPZ6438 that inhibit EZH2 specifically by competitive binding at the S-adenosylmethionine (SAM) binding site in combination with the common second-line chemotherapeutic oxaliplatin. The change in cytotoxic effects under pharmacological EZH2 inhibition was evaluated revealing a drastic increase in oxaliplatin resistance after 72 h and longer periods of combinational incubation. This outcome was independent of cell type but associated to reduced intracellular platinum. Pharmacological EZH2 inhibition revealed increased expression in SRE binding proteins, SREBP1/2 and ATP binding cassette subfamily G transporters ABCG1/2. The latter are associated with chemotherapy resistance due to increased platinum efflux. Knockdown experiments revealed that this was independent of the EZH2 functional state. The EZH2 inhibition effect on oxaliplatin resistance and efflux was reduced by additional inhibition of the regulated target proteins. In conclusion, pharmacological EZH2 inhibition is not suitable in combination with the common chemotherapeutic oxaliplatin in T-cell lymphomas revealing an EZH2-independent off-target effect.

Keywords

EZH2; EZH2 inhibitors; T-cell leukemia; chemotherapy; combination therapy; drug resistance; mature T-cell lymphoma; oxaliplatin.

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