Chromosome-arm 17p Loss Renders Breast Cancer Cells Vulnerable to AURKB Inhibition

Abstract

Loss of chromosome-arm 17p (Del17p) is a genetic hallmark of breast cancer. While TP53 loss is an established driver of Del17p, the potential therapeutically-relevant cellular vulnerabilities of this common aneuploidy remain unexplored. Here, we first analyzed genomic and clinical data from breast cancer patients using METABRIC and TCGA datasets. Del17p was prevalent across molecular subtypes and correlated with higher tumor grade, advanced stage, and worse survival. Gene expression profiling revealed reduced expression and activity of the chromosome 17p-residing gene Aurora Kinase B (AURKB) in Del17p tumors and cell lines. Moreover, functional dependency screens across breast cancer cell lines identified increased sensitivity of Del17p cells to genetic inhibition of AURKB, which we validated using chemical inhibition in matched breast cancer cell lines. Next, we generated an isogenic model of CAL51 breast cancer cells with/without heterozygous AURKB loss in TP53-WT and TP53-null backgrounds, and confirmed that heterozygous loss of AURKB resulted in its reduced expression and in increased sensitivity to the AURKB inhibitor barasertib. Notably, p53 inactivation increased AURKB expression and reduced drug sensitivity, as previously reported, but AURKB heterozygous knockout reverted these phenotypes, revealing opposite effects of common modes of p53 inactivation (Del17p vs. point mutations). Mechanistically, the phenotypes associated with barasertib treatment - mitotic aberrations, cytokinesis failure, whole-genome doubling and apoptosis - were exacerbated in Del17p cells. Our findings therefore suggest Del17p as a potential biomarker for identifying breast cancer patients who may benefit from AURKB inhibition and highlight its potential as a therapeutic target in Del17p breast tumors. SignificanceBreast cancer tumors with loss of chromosome-arm 17p (Del17p) exhibit reduced AURKB expression and increased sensitivity to AURKB inhibition, suggesting Del17p as a biomarker for AURKB-targeted therapy.