CREBBP（编码组蛋白乙酰转移酶）的功能丧失突变经常发生在 B 细胞恶性肿瘤中，这凸显了 CREBBP 缺陷是一个有吸引力的治疗靶点。使用已建立的等基因细胞模型，我们证明了 CREBBP 缺陷的细胞选择性地容易受到 AURKA 抑制的影响。从机制上讲，我们发现共同靶向 CREBBP 和 AURKA 抑制 MYC 转录和翻译后，从而诱导复制应激和细胞凋亡。抑制 AURKA 会显着降低 CREBBP 缺陷细胞中的 MYC 蛋白水平，这意味着依赖 AURKA 来维持 MYC 稳定性。此外，体内研究表明，AURKA 的药理学抑制可有效延缓 CREBBP 缺陷细胞中的肿瘤进展，并且在 CREBBP 丰富的细胞中与 CREBBP 抑制剂具有协同作用。我们的研究揭示了 CREBBP 和 AURKA 之间的新型合成致死相互作用，表明针对 AURKA 代表了针对含有 CREBBP 失活突变的高风险 B 细胞恶性肿瘤的潜在治疗策略。© 2024。作者，获得独家许可施普林格自然有限公司。

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.