Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer.
Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer.
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使用DDX3和PARP抑制剂的联合处理可诱导BRCA1乳腺癌的合成致死性。
DOI：
10.1007/s12032-017-0889-2
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Raman V
中科院分区：
文献类型：
--
作者：
Heerma van Voss MR;Brilliant JD;Vesuna F;Bol GM;van der Wall E;van Diest PJ;Raman V
三阴性乳腺癌由于其固有的侵袭行为和缺乏靶向治疗而具有不利的结果。 BRCA1 突变携带者中发生的乳腺癌大多是三阴性的，并具有同源重组缺陷，使它们对 PARP 抑制剂等第二条 DNA 损伤修复途径的抑制敏感。不幸的是，BRCA1 缺陷型癌症中对 PARP 抑制剂的耐药性很常见，而 BRCA1 丰富型乳腺癌中的敏感性有限。 RK-33 是 RNA 解旋酶 DDX3 的抑制剂，此前已被证明可以阻碍 DNA 断裂的非同源末端连接修复。因此，我们评估了 DDX3 作为 BRCA 促乳腺癌和 BRCA 缺陷乳腺癌的治疗靶点，并评估了 DDX3 抑制是否可以使细胞对 PARP 抑制敏感。通过免疫组织化学检测发现，24% 的 BRCA1 突变携带者 (p = 0.337) 和 21% 的 BRCA2 突变携带者 (p = 0.624) 乳腺癌样本中 DDX3 高表达，而散发性乳腺癌样本中这一比例为 30%。在 BRCA1 亲和缺陷乳腺癌细胞系中，对 DDX3 抑制剂 RK-33 的敏感性相似，IC50 值在低微摩尔范围内 (2.8–6.6 μM)。在 BRCA1 表达的乳腺癌中，观察到 RK-33 和 PARP 抑制剂奥拉帕尼联合治疗存在协同相互作用，平均联合指数范围为 0.59 至 0.62。总体而言，我们得出的结论是，BRCA 促进型乳腺癌和 BRCA 缺陷型乳腺癌对 DDX3 具有相似的依赖性。 RK-33 抑制 DDX3 与 PARP 抑制剂治疗具有协同作用，尤其是在 BRCA1 背景丰富的乳腺癌中。
Triple-negative breast cancers have unfavorable outcomes due to their inherent aggressive behavior and lack of targeted therapies. Breast cancers occurring in BRCA1 mutation carriers are mostly triple-negative and harbor homologous recombination deficiency, sensitizing them to inhibition of a second DNA damage repair pathway by, e.g., PARP inhibitors. Unfortunately, resistance against PARP inhibitors in BRCA1-deficient cancers is common and sensitivity is limited in BRCA1-proficient breast cancers. RK-33, an inhibitor of the RNA helicase DDX3, was previously demonstrated to impede non-homologous end-joining repair of DNA breaks. Consequently, we evaluated DDX3 as a therapeutic target in BRCA pro- and deficient breast cancers and assessed whether DDX3 inhibition could sensitize cells to PARP inhibition. High DDX3 expression was identified by immunohistochemistry in breast cancer samples of 24% of BRCA1 (p = 0.337) and 21% of BRCA2 mutation carriers (p = 0.624), as compared to 30% of sporadic breast cancer samples. The sensitivity to the DDX3 inhibitor RK-33 was similar in BRCA1 pro- and deficient breast cancer cell lines, with IC50 values in the low micromolar range (2.8–6.6 μM). A synergistic interaction was observed for combination treatment with RK-33 and the PARP inhibitor olaparib in BRCA1-proficient breast cancer, with the mean combination index ranging from 0.59 to 0.62. Overall, we conclude that BRCA pro-and deficient breast cancers have a similar dependency upon DDX3. DDX3 inhibition by RK-33 synergizes with PARP inhibitor treatment, especially in breast cancers with a BRCA1-proficient background.
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影响因子：
3.7
作者：
Bol GM;Raman V;van der Groep P;Vermeulen JF;Patel AH;van der Wall E;van Diest PJ
通讯作者：
van Diest PJ
影响因子：
8
作者：
Botlagunta, M.;Vesuna, F.;Raman, V.
通讯作者：
Raman, V.
影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1099/vir.0.015909-0
发表时间：
2010-01
期刊：
The Journal of general virology
影响因子：
--
作者：
Angus AG;Dalrymple D;Boulant S;McGivern DR;Clayton RF;Scott MJ;Adair R;Graham S;Owsianka AM;Targett-Adams P;Li K;Wakita T;McLauchlan J;Lemon SM;Patel AH
通讯作者：
Patel AH
影响因子：
6.6
作者：
Moelans, Cathy B.;de Weger, Roel A.;van Diest, Paul J.
通讯作者：
van Diest, Paul J.