Dynamin impacts homology-directed repair and breast cancer response to chemotherapy
Dynamin impacts homology-directed repair and breast cancer response to chemotherapy
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DOI：
10.1172/jci87191
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发表时间：
2018-12-03
影响因子：
15.9
通讯作者：
Brown, J. Martin
中科院分区：
文献类型：
--
作者：
Chernikova, Sophia B.;Nguyen, Rochelle B.;Brown, J. Martin
三阴性乳腺癌(TNBCs)在化疗开始有效后，通常复发为化疗耐药肿瘤，这与上调的同源基因定向修复(HDR)有关。因此，HDR的抑制剂可能是化疗治疗这些癌症的有用辅助药物。我们进行了HDR抑制剂的高通量化学筛选，从中我们获得了一些扰乱微管动力学的命中结果。我们推测，肿瘤中筛查的靶分子水平高与化疗反应差有关。我们发现，抑制或敲除动力蛋白2(DNM2)，其在细胞内运输和微管动力学中的作用，损害了小鼠的细胞和肿瘤的HDR和改善对化疗的反应。在一项回顾分析中，治疗时DNM2水平强烈预测雌激素受体阴性患者的化疗结果，特别是对TNBC患者。我们认为，DNM2相关的DNA修复酶转运对HDR效率很重要，是预测乳腺癌化疗敏感性的有力指标，也是治疗的重要靶点。
After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy.