Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma.
Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma.
复制标题
靶向BRD2和BRD3蛋白联合抑制PI3K-AKT作为卵巢透明细胞癌的治疗策略
DOI：
10.1158/1535-7163.mct-20-0809
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发表时间：
2021-04
影响因子：
5.7
通讯作者：
Kemp CJ
中科院分区：
文献类型：
--
作者：
Shigeta S;Lui GYL;Shaw R;Moser R;Gurley KE;Durenberger G;Rosati R;Diaz RL;Ince TA;Swisher EM;Grandori C;Kemp CJ
卵巢透明细胞癌（OCCC）是一种罕见的卵巢癌，化疗耐药亚型。为了确定OCCC的新治疗靶点和联合治疗，我们对一组患者来源的卵巢癌细胞系进行了阵列化高通量siRNA和药物筛选。结果表明，OCCC细胞易受表观遗传基因靶标如布罗莫结构域和末端外结构域（BET）蛋白BRD 2和BRD 3的敲低的影响。随后的RNA干扰测定以及BET抑制剂处理验证了这些BET蛋白作为潜在的治疗靶标。由于对单一靶向药物的耐药性的发展是常见的，我们接下来进行了敏化剂药物筛选，以确定与BET抑制剂CPI 0610的潜在联合治疗。几种PI 3 K或AKT抑制剂是鉴定的最佳药物组合，随后的工作显示CPI 0610通过诱导p53非依赖性细胞凋亡与alpelisib或MK 2206协同作用。我们进一步验证了CPI 0610和PI 3 K-AKT通路抑制剂alpelisib、MK2206或ipatasertib在直接从OCCC患者获得的肿瘤类器官中的协同作用。这些发现表明，有必要对BET抑制剂单独或与PI 3 K-AKT抑制剂联合用于OCCC进行进一步的临床前评价。
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K-AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from OCCC patients. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC is warranted.