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

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 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 DLBCL harboring CREBBP inactivating mutations. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for CREBBP and H3K27ac in SC1 cells. Overall design: Yichen,Sun