Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Protein phosphatase 2A (PP2A) is a tumor suppressor, but its activity is often inhibited in human cancers.
• MYC proto-oncogene (MYC) overexpression is linked to aggressive cancers, and PP2A directly dephosphorylates MYC, leading to its degradation.

Purpose of the Study:

• To investigate the therapeutic potential of activating PP2A using small-molecule activators of PP2A (SMAPs) in various MYC-driven cancers.
• To assess the efficacy of SMAPs in inhibiting MYC expression and subsequent cancer progression.

Main Methods:

• Biochemical assays, recombinant cell lines, gene expression analysis, and immunohistochemistry were employed.
• SMAPs were tested in models of Burkitt lymphoma, KRAS-driven non-small cell lung cancer, and triple-negative breast cancer.
• Cell lines with PP2A-dependent phosphodegron variants of MYC were generated to confirm MYC degradation dependency.

Main Results:

• SMAP treatment led to rapid and sustained inhibition of MYC expression via proteasome-mediated degradation in all tested MYC-driven cancer models.
• SMAP treatment inhibited MYC transcriptional activity, decreased cancer cell proliferation, and reduced tumor growth.
• The antitumorigenic effects of SMAPs were confirmed to be dependent on MYC degradation.

Conclusions:

• Direct PP2A activation with SMAPs represents a pharmacologically viable strategy for managing a wide spectrum of MYC-driven cancers.
• Targeting MYC degradation through PP2A activation offers a promising therapeutic avenue for aggressive cancers characterized by MYC overexpression.