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

摘要 三阴性乳腺癌（TNBC）的特征在于高的p53突变率（高达80%）和广泛的 染色体不稳定性（CIN）。这种高CIN是一种潜在的脆弱性，因为过度CIN可导致细胞死亡 和肿瘤抑制。因此，一种潜在的方法是通过靶向治疗将癌症中的CIN提高到毒性水平。 有丝分裂中控制正常染色体分离的因素。TNBC和其他具有高基础CIN的癌症 可能特别容易受到这种方法的影响。 极光激酶B（Aurora kinase B，AURKB）在纺锤体组装过程中起重要作用，是一个潜在的靶点 检查点和有丝分裂。AURKB抑制剂Barasertib-HQPA（AZD 2811）正在进行临床试验。组蛋白 甲基转移酶SUV 4 - 20 H也通过控制染色体的甲基化来调节染色体的分离和稳定性。 甲基化和着丝粒附近的异染色质状态。在目前的拨款中，我们筛选了巴拉塞提， 与各种组蛋白修饰抑制剂组合用于在乳腺癌细胞中存活。我们找到barasertib了 与SUV 4 - 20 H抑制剂A196组合在p53缺陷或突变的小鼠中引起明显的合成致死性。 p53 WT细胞而不是p53 WT细胞。在乳腺癌亚型中，TNBC细胞对此非常敏感。 药物组合。这项资助的目的是测试这种药物组合对TNBC细胞的潜力 和肿瘤，并确定所涉及的机制。 在第一个目标中，我们将通过以下方式测试barasertib + A196在TNBC细胞中诱导合成致死性的模型： 增加CIN。TNBC细胞表达高水平的转录因子ETS 1/ETS 2和ras效应蛋白 RASSF 8，我们的初步数据表明，这些因素促进TNBC细胞对barasertib + A196在目标2中，我们将敲除或过表达这些因子，以检测它们在barasertib + A196中的作用 灵敏度目标3将测试barasertib + A196药物组合有效靶向TNBC的能力 小鼠的肿瘤 这些研究的阳性结果将支持AURKB和SUV 4 - 20 H联合抑制作为潜在的 p53突变TNBC的治疗方法。积极的结果也将揭示SUV 4 - 20 H作为治疗目标， 在TNBC中诱导毒性CIN，并可能导致其他癌症。

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.