Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage

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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

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Maolin Ge1, Qiongyu Xu1, Ting Kang2

  • 1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cancer Science
|March 19, 2021
PubMed

Insights

Cyclin A1 suppression causes drug tolerance in leukemia cells, leading to relapse. Combination therapy with proteasome inhibitors and deubiquitinating enzyme inhibitors restores cyclin A1, overcoming resistance and preventing cancer recurrence.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Drug resistance is a major challenge in cancer therapy, often arising from reversible drug-tolerant cells.
  • Understanding adaptive responses in drug-tolerant cancer cells is crucial for preventing relapse.
  • Mechanisms of resistance to proteasome inhibitors (PIs) are not fully understood.

Purpose of the Study:

  • To investigate the role of cyclin A1 in the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells.
  • To elucidate the adaptive mechanisms underlying PI resistance in MLL cells.
  • To identify potential therapeutic strategies to overcome PI resistance.

Main Methods:

  • Investigated cyclin A1 suppression and its effect on PI tolerance in MLL cells.
  • Analyzed cell-cycle arrest and cyclin A1 dependency in PI-tolerant cells.
  • Examined the impact of combination therapy with PI and deubiquitinating enzyme (DUB) inhibitors on cyclin A1 expression and drug resistance.
  • Studied chromatin crosstalk involving histone modifications and MLL protein.

Main Results:

  • Cyclin A1 suppression induced transient PI tolerance in MLL cells via cell-cycle arrest.
  • PI-tolerant MLL cells exhibited cyclin A1 dependency, regulated by MLL protein.
  • Loss of cyclin A1 function correlated with patient relapse and reduced survival.
  • Combination therapy with PI and DUB inhibitors restored cyclin A1 expression by targeting epigenetic mechanisms.
  • This combination therapy overcame PI resistance in MLL cells.

Conclusions:

  • Cyclin A1-mediated cell-cycle regulation is critical in PI resistance in MLL cells.
  • Reversible downregulation of cyclin A1 contributes to acquired drug tolerance and relapse.
  • DUB inhibitors promoting cell-cycle re-entry represent a potential epigenetic strategy to combat acquired drug resistance.
  • Targeting cyclin A1 and epigenetic pathways offers a promising approach to prevent cancer treatment failure.
Keywords:
cyclin A1deubiquitinating enzyme inhibitordrug tolerancemixed-linage leukemiaproteasome inhibitor

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