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Targeting AURKA to induce synthetic lethality in CREBBP-deficient DLBCL via attenuation of MYC expression

GSE211451 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2025/05/13 Platform GPL24676
Summary
Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in diffuse large B-cell lymphoma (DLBCL), highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic DLBCL 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 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 DLBCL harboring CREBBP inactivating mutations.
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Also filed as BioProject PRJNA870433 and SRA study SRP392678. Searching any of these in the dataset finder brings you back here.

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