Histone acetyltransferases (HATs) are implicated as both oncogene and nononcogene dependencies in diverse human cancers. Acetyl-CoA-competitive HAT inhibitors have emerged as potential cancer therapeutics and the first clinical trial for this class of drugs is ongoing (NCT04606446). Despite these developments, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. Having discovered that multiple regulators of de novo coenzyme A (CoA) biosynthesis can modulate sensitivity to CBP/p300 HAT inhibition (PANK3, PANK4 and SLC5A6), we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance. This not only affects structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B HAT inhibitor that is currently in Phase 1 clinical trials. Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new form of targeted therapy.

组蛋白乙酰转移酶 (HAT) 在多种人类癌症中既依赖于癌基因，也依赖于非癌基因。乙酰辅酶A竞争性 HAT 抑制剂已成为潜在的癌症治疗药物，此类药物的首次临床试验正在进行中 (NCT04606446)。尽管取得了这些进展，但治疗反应和耐药性的潜在机制仍然知之甚少。我们发现辅酶 A (CoA) 生物合成的多个调节因子可以调节对 CBP/p300 HAT 抑制（PANK3、PANK4 和 SLC5A6）的敏感性，因此我们确定升高的乙酰辅酶 A 浓度可以胜过药物靶点结合，从而引发获得性耐药性。这不仅影响结构多样的 CBP/p300 HAT 抑制剂，还影响与目前处于 1 期临床试验的研究性 KAT6A/B HAT 抑制剂相关的药物。总而言之，这项工作揭示了 CoA 代谢是抗癌 HAT 抑制剂的一个意想不到的缺点，因此将有利于未来优化这种新型靶向治疗的功效。