A synthetic lethal approach for targeting p53 deficient triple negative breast cancer

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Abstract Triple negative breast cancer (TNBC) is characterized by a high rate of p53 mutation (up to 80%) and widespread chromosome instability (CIN). This high CIN is a potential vulnerability as excessive CIN can lead to cell death and tumor suppression. A potential approach therefore is to elevate CIN in cancer to toxic levels by targeting factors that control normal chromosome segregation in mitosis. TNBCs and other cancers with high basal CIN may be especially susceptible to such approaches. Aurora kinase B (AURKB) is a potential target to elevate CIN in cancer due to its roles in the spindle assembly checkpoint and mitosis. The AURKB inhibitor Barasertib-HQPA (AZD2811) is in current clinical trials. The histone methyltransferase SUV4-20H also regulates chromosome segregation and stability by controlling the methylation and heterochromatin state near centromeres. In the current grant, we screened barasertib in combination with various histone modification inhibitors for survival in breast cancer cells. We found barasertib combined with the SUV4-20H inhibitor A196 caused pronounced synthetic lethality in p53-deficient or mutated cells but not p53 WT cells. Among breast cancer sub-types, TNBC cells were strikingly hypersensitive to this drug combination. The purpose of this grant is to test the potential of this drug combination against TNBC cells and tumors, and to determine the mechanisms involved. In the first aim we will test the model that barasertib plus A196 induces synthetic lethality in TNBC cells by increasing CIN. TNBC cells express high levels of transcription factors ETS1/ETS2 and the ras effector protein RASSF8, and our preliminary data suggest these factors promote sensitivity of TNBC cells to barasertib plus A196. In Aim 2 we will knockdown or overexpress these factors to test their role in barasertib plus A196 sensitivity. In Aim 3 will test the ability of the barasertib plus A196 drug combination to effectively target TNBC tumors in mice. Positive results from these studies will support combined AURKB and SUV4-20H inhibition as a potential therapeutic approach for p53 mutant TNBC. Positive results will also reveal SUV4-20H as a therapy target to induce toxic CIN in TNBC, and potentially other cancers.