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Dual targeting of MCL1 and NOXA as effective strategy for treatment of mantle cell lymphoma

Elisabeth Höring1,2,3, Arnau Montraveta3, Simon Heine1

  • 1Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.

British Journal of Haematology
|March 16, 2017
PubMed

Insights

Combining fatty acid synthase inhibitors and Dinaciclib synergistically targets the NOXA/MCL1 axis, inducing apoptosis and inhibiting mantle cell lymphoma (MCL) progression. This dual-targeting strategy shows promise for MCL therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Imbalances in BCL2 protein family composition drive mantle cell lymphoma (MCL) development and treatment resistance.
  • BCL2 family proteins represent promising therapeutic targets in MCL.

Purpose of the Study:

  • To investigate the efficacy of dual targeting the NOXA/MCL1 axis in MCL.
  • To evaluate the combination of fatty acid synthase (FAS) inhibitors and the CDK inhibitor Dinaciclib for MCL treatment.

Main Methods:

  • Utilized cell lines and primary MCL cells for in vitro studies.
  • Employed a mouse model to assess in vivo tumor progression.
  • Combined FAS inhibitors (for NOXA stabilization) with Dinaciclib (for MCL1 reduction).

Main Results:

  • The combination therapy synergistically induced apoptosis in MCL cell lines and primary cells.
  • Tumor progression was almost completely inhibited in a mouse model.
  • Apoptosis induction was dependent on NOXA and correlated with the NOXA/MCL1 ratio.

Conclusions:

  • The NOXA/MCL1 balance is critical for effective apoptosis induction in MCL.
  • Dual targeting of the NOXA/MCL1 axis represents a potent therapeutic strategy for mantle cell lymphoma.
Keywords:
DinaciclibFASNiMCL1NOXAmantle cell lymphoma

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