Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition

Area of Science:

• Molecular Oncology
• Cancer Therapeutics
• Drug Resistance Mechanisms

Background:

• Histone acetyltransferases (HATs) are crucial in cancer development and are targeted by novel therapeutics.
• The first clinical trials for acetyl-CoA-competitive HAT inhibitors are underway, showing therapeutic promise.
• Understanding mechanisms of therapeutic response and drug resistance is critical for optimizing HAT inhibitor efficacy.

Purpose of the Study:

• To investigate the role of de novo coenzyme A (CoA) biosynthesis regulators in modulating sensitivity to HAT inhibitors.
• To elucidate the mechanisms by which acquired drug resistance develops against HAT inhibitors.
• To identify potential liabilities and strategies for enhancing the efficacy of anticancer HAT inhibitors.

Main Methods:

• Identified regulators of de novo CoA biosynthesis (PANK3, PANK4, SLC5A6) influencing sensitivity to CBP/p300 HAT inhibition.
• Investigated the impact of elevated acetyl-CoA concentrations on drug-target engagement for HAT inhibitors.
• Assessed the effect of acetyl-CoA on structurally diverse CBP/p300 HAT inhibitors and investigational KAT6A/B inhibitors.

Main Results:

• Multiple regulators of de novo CoA biosynthesis were found to modulate sensitivity to CBP/p300 HAT inhibition.
• Elevated acetyl-CoA concentrations were shown to outcompete drug-target engagement, leading to acquired drug resistance.
• This resistance mechanism affects both CBP/p300 and KAT6A/B HAT inhibitors, including those in clinical trials.

Conclusions:

• Coenzyme A (CoA) metabolism represents an unexpected vulnerability in the therapeutic strategy of anticancer HAT inhibitors.
• Elevated acetyl-CoA is a key mechanism driving acquired resistance to structurally diverse HAT inhibitors.
• Targeting CoA metabolism offers a potential avenue for optimizing the efficacy and overcoming resistance to HAT inhibitor-based cancer therapies.