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乙酰辅酶 A 生物合成驱动对组蛋白乙酰转移酶抑制剂的耐药性。

Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition.

机构信息

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA.

出版信息

Nat Chem Biol. 2023 Oct;19(10):1215-1222. doi: 10.1038/s41589-023-01320-7. Epub 2023 May 1.

DOI:10.1038/s41589-023-01320-7
PMID:37127754
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10538425/
Abstract

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.

摘要

组蛋白乙酰转移酶 (HATs) 被认为是多种人类癌症中的癌基因和非癌基因依赖性。乙酰辅酶 A 竞争性 HAT 抑制剂已成为潜在的癌症治疗药物，该类药物的首次临床试验正在进行中（NCT04606446）。尽管有这些进展，但治疗反应和演变耐药性的潜在机制仍知之甚少。我们发现从头合成辅酶 A (CoA) 的多个调节剂可以调节对 CBP/p300 HAT 抑制的敏感性（PANK3、PANK4 和 SLC5A6），我们确定升高的乙酰辅酶 A 浓度可以与药物靶标竞争，从而产生获得性耐药性。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 KAT6A/B HAT 抑制剂相关的药物。总之，这项工作揭示了 CoA 代谢作为抗癌 HAT 抑制剂的一个意外缺陷，因此将为优化这种新型靶向治疗的疗效提供未来的努力。

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