Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells.
Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells.
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DOI：
10.1371/journal.pone.0235025
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Parvin JD
中科院分区：
文献类型：
--
作者：
Moustafa D;Elwahed MRA;Elsaid HH;Parvin JD
三阴性乳腺癌（TNBC）约占所有乳腺癌的10-15%，由于缺乏治疗的受体靶点，结果不佳，并且TNBC通常与BRCA 1的生殖系突变相关。聚（ADP-核糖）聚合酶抑制剂（PARPi）药物在治疗BRCA 1或BRCA 2突变的乳腺癌和卵巢癌方面表现出一定的有效性，但对PARPi的耐药性很常见。已发表的结果发现，对奥拉帕尼（一种PARPi）的耐药性可能是由于EMI 1的下调和随后的RAD 51重组酶的上调。使用基于组织培养的细胞活力测定，我们将这些观察结果扩展到另一种PARPi和其他影响DNA修复或细胞周期的化疗药物。正如我们所料，EMI 1下调导致对另一种PARPi药物Talazoparib的耐药性。EMI 1下调也导致对其他细胞毒性药物、顺铂和CHK 1抑制剂的耐药性。值得注意的是，增加RAD 51蛋白表达仅概括了EMI 1消耗在赋予细胞对不同PARPi和其他细胞毒性药物的抗性中的一些但不是全部作用。这些结果表明，有助于PARPi抗性的EMI 1下调的下游效应是增加细胞中RAD 51蛋白的浓度并阻断有丝分裂进入。我们发现，即使在EMI 1表达下调时，CHK 1抑制剂与奥拉帕尼组合也会导致敏感性恢复。这种联合疗法可能是克服BRCA 1缺陷型TNBC细胞中PARPi抗性的手段。
Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.
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