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 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. Overall design: RNA-seq for SC1 treated with DMSO, alisertib, SGC-CBP30 and combination was performed (duplicate).