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Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug

Elisabetta Mereu1, Damiano Abbo1, Tina Paradzik1,2

  • 1Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.

Cancers
|May 16, 2023
PubMed

Insights

Inhibiting EHMT2 (euchromatic histone-lysine N-methyltransferase 2) with UNC0642 enhances proteasome inhibitor efficacy in multiple myeloma, overcoming drug resistance and improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Proteasome inhibitors (PIs) are crucial for multiple myeloma (MM) therapy but face challenges with drug resistance and toxicity.
  • Intrinsic or acquired resistance to PIs limits their long-term effectiveness in MM patients.
  • Adverse effects like peripheral neuropathy and cardiotoxicity necessitate alternative therapeutic strategies.

Purpose of the Study:

  • To identify novel compounds that can potentiate the efficacy of proteasome inhibitors in multiple myeloma.
  • To investigate the therapeutic potential of targeting EHMT2 (euchromatic histone-lysine N-methyltransferase 2) in combination with PIs.
  • To explore the mechanisms underlying the synergistic effects of EHMT2 inhibition and PI treatment in MM.

Main Methods:

  • Functional screening of small-molecule inhibitors targeting key signaling pathways to identify synergistic interactions with PIs.
  • In vitro testing of the EHMT2 inhibitor UNC0642 in combination with carfilzomib (CFZ) across diverse MM cell lines, including resistant models.
  • Assessment of cytotoxicity on normal cells (PBMCs, bone-marrow-derived stromal cells) and validation using an alternative EHMT2 inhibitor.

Main Results:

  • The EHMT2 inhibitor UNC0642 demonstrated synergistic cytotoxicity with carfilzomib (CFZ) in multiple myeloma cell lines, including drug-resistant ones.
  • Elevated EHMT2 expression in MM patients correlated with poorer survival and increased resistance to bortezomib.
  • The combination treatment showed a favorable safety profile on normal hematopoietic and stromal cells and perturbed autophagy and DNA damage repair pathways.

Conclusions:

  • EHMT2 inhibition represents a promising strategy to enhance the sensitivity of multiple myeloma to proteasome inhibitors.
  • Targeting EHMT2 can overcome acquired resistance to PIs, offering a potential new therapeutic avenue for MM patients.
  • The combination of EHMT2 inhibitors and PIs exhibits a multi-layered mechanism of action, impacting critical cellular processes.
Keywords:
EHMT2combinatorial treatmentdrug resistancefunctional screeningmultiple myelomaproteasome inhibitors

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