Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Loss-of-function mutations in CREBBP (CREB-binding protein), a histone acetyltransferase, are prevalent in B-cell malignancies.
• CREBBP deficiency presents a potential therapeutic vulnerability in these cancers.

Purpose of the Study:

• To investigate the therapeutic potential of targeting AURKA (Aurora Kinase A) in CREBBP-deficient B-cell malignancies.
• To elucidate the mechanistic link between CREBBP deficiency, AURKA inhibition, and cancer cell survival.

Main Methods:

• Utilized isogenic cell models to assess the selective vulnerability of CREBBP-deficient cells to AURKA inhibition.
• Investigated the molecular mechanisms, including MYC regulation, underlying the observed synthetic lethality.
• Conducted in vivo studies using pharmacological inhibition of AURKA in preclinical models.

Main Results:

• CREBBP-deficient cells exhibit selective sensitivity to AURKA inhibition.
• Co-targeting CREBBP and AURKA leads to transcriptional and post-translational suppression of MYC, inducing replication stress and apoptosis.
• AURKA inhibition significantly reduces MYC protein levels in CREBBP-deficient cells, suggesting a role in MYC stabilization.
• Pharmacological AURKA inhibition demonstrated efficacy in delaying tumor progression in vivo and showed synergy with CREBBP inhibitors.

Conclusions:

• Identified a novel synthetic lethal interaction between CREBBP and AURKA.
• Targeting AURKA represents a promising therapeutic strategy for B-cell malignancies with CREBBP inactivating mutations.