Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Therapeutics

Background:

• Polycomb repressive complex 2 (PRC2) and PI3K/Akt signaling are key therapeutic targets in multiple myeloma.
• The precise interactions between these pathways remain incompletely understood.
• Elucidating these crosstalk mechanisms is crucial for developing effective combination therapies.

Purpose of the Study:

• To investigate the epigenetic interactions following Akt inhibition in multiple myeloma.
• To evaluate the efficacy of combined inhibition of Akt and PRC2 components.
• To understand the compensatory mechanisms involving EZH1 and the role of FOXO signaling.

Main Methods:

• Utilized TAS-117 (Akt inhibitor) and UNC1999/GSK126 (PRC2 inhibitors).
• Performed mRNA and protein level analysis, RNA-sequencing, and Chromatin Immunoprecipitation (ChIP) assays.
• Investigated effects on cytotoxicity, apoptosis, and gene expression, including FOXO signaling pathway.

Main Results:

• Akt inhibition by TAS-117 downregulated EZH2 but led to compensatory EZH1 upregulation.
• Dual inhibition of Akt and PRC2 (using UNC1999) synergistically enhanced anti-myeloma cytotoxicity and apoptosis.
• TAS-117 treatment activated FOXO signaling, with FOXO3 directly binding and enhancing EZH1 promoter activity.

Conclusions:

• Akt inhibition influences epigenetic regulators, specifically PRC2 components, in multiple myeloma.
• Combined targeting of Akt and full PRC2 activity demonstrates significant therapeutic potential.
• Understanding the Akt-FOXO-EZH1 axis offers new avenues for multiple myeloma treatment strategies.