Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• High-risk myelodysplastic syndromes (MDS) have limited treatment options, with azacitidine (AZA) showing partial efficacy but frequent relapse.
• Novel therapeutic strategies are crucial to improve outcomes for MDS patients.

Purpose of the Study:

• To identify novel regulators of AZA sensitivity in MDS.
• To explore combination therapies involving AZA and inhibitors of identified regulators.

Main Methods:

• Loss-of-function shRNA screening to identify key regulators of AZA sensitivity.
• Testing the synergistic effects of CBP/p300 inhibitors combined with AZA on MDS-derived AML cell lines.
• Investigating the mechanism of action, including AZA's RNA-dependent functions and protein synthesis inhibition.

Main Results:

• CREB binding protein (CBP) was identified as a critical regulator of AZA sensitivity.
• Inhibitors of CBP and p300 synergistically reduced the viability of MDS-derived AML cells when combined with AZA.
• The observed synergy was specific to the RNA-dependent effects of AZA, unlike decitabine.
• CBP/p300 inhibition was found to downregulate global protein synthesis.

Conclusions:

• CBP is a key determinant of AZA response in MDS.
• Targeting CBP/p300 activity represents a promising therapeutic strategy to enhance AZA efficacy in MDS.
• The mechanism involves the downregulation of protein synthesis, highlighting a novel therapeutic pathway.