Coinhibition of Aurora Kinase B and SUV4-20H Induces Synthetic Lethality in Wild-type p53-Deficient Cancer Cells

The tumor suppressor p53 is inactivated by mutation or deletion in more than half of all human cancers. Wild-type p53 induces a G1-phase arrest when activated to halt cell proliferation and division. Accordingly, p53-mutated or -deficient cancers may be especially sensitive to agents that target proliferating and/or dividing cells. Barasertib (AZD2811) targets the mitotic Aurora kinase B and is in current clinical trials for various cancers. SUV4-20H1 and H2 are histone methyltransferases that can affect mitosis by regulating chromatin compaction in and around centromeres. The drug A196 inhibits SUV4-20H1 and H2. In the current study, we found combined treatment with barasertib plus A196 induces a pronounced synthetic lethality effect in p53-deficient cancer cells. Mechanistically, we found barasertib plus A196 kills p53-deficient cells by inhibiting the spindle assembly checkpoint and inducing massive chromosome missegregations and toxic aneuploidy. Among breast cancer subtypes, triple-negative breast cancer cells were the most sensitive to this drug combination. Lastly, we found in two different p53-mutated cell line tumor models that barasertib plus A196 has greater antitumor activity than either single agent. Our results suggest cotargeting of Aurora kinase B and SUV4-20H1/2 could be effective against p53-mutated or -deficient cancers, including triple-negative breast cancers in which approximately 80% of cases are p53-mutated.