PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.
PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.
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DOI：
10.1158/1535-7163.mct-18-0177
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发表时间：
2018-12
影响因子：
5.7
通讯作者：
Wakimoto H
中科院分区：
文献类型：
--
作者：
Higuchi F;Fink AL;Kiyokawa J;Miller JJ;Koerner MVA;Cahill DP;Wakimoto H
通过MSH6失活导致的错配修复(MMR)缺陷在多达30%的复发高级别胶质瘤中被发现，这是导致对烷化剂替莫唑胺(TMZ)产生获得性耐药的关键分子机制。为了开发一种对TMZ耐药的胶质瘤有效的治疗策略，我们首先筛选了13种DNA损伤反应调节剂，以了解它们抑制MSH6灭活的、TMZ耐药的胶质瘤细胞的能力。我们发现PLK1选择性抑制剂Volasertib是最有效的抑制胶质母细胞瘤细胞增殖的药物。PLK1抑制导致胶质母细胞瘤细胞有丝分裂灾难、G2/M期细胞周期停滞和DNA损伤，导致caspase介导的细胞凋亡。重要的是，PLK1抑制剂的治疗效果不受MSH6基因敲除的影响，这表明它们的作用与细胞的MMR状态无关。在MMR缺乏、TMZ耐药的胶质母细胞瘤异种移植模型中，Volasertib的全身治疗有效地抑制了肿瘤的生长。此外，在已建立的和患者来源的细胞系面板中进行的体外测试显示，PLK1抑制剂的有效性与细胞Myc的表达状态有关。我们发现，Myc基因失控的细胞容易受到PLK1抑制，因为Myc的过度表达使其变得敏感，而其沉默使胶质母细胞瘤细胞对PLK1抑制剂不敏感。这一发现在临床上是相关的，因为TMZ治疗后的胶质瘤进展经常伴随着MYC基因组扩增和/或通路激活。总之，PLK抑制剂代表了一种新的治疗复发性胶质瘤的选择，包括那些因MMR缺陷而对TMZ耐药的胶质瘤。基因组MYC的改变可以作为PLK抑制剂敏感性的生物标志物，因为Myc驱动的肿瘤表现出明显的反应。
Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in up to 30% of recurrent high-grade gliomas, and represents a key molecular mechanism underlying the acquired resistance to the alkylating agent temozolomide (TMZ). To develop a therapeutic strategy that could be effective in these TMZ-refractory gliomas, we first screened 13 DNA damage response modulators for their ability to suppress viability of MSH6-inactivated, TMZ-resistant glioma cells. We identified a PLK1 selective inhibitor, Volasertib, as the most potent in inhibiting proliferation of glioblastoma cells. PLK1 inhibition induced mitotic catastrophe, G2/M cell cycle arrest, and DNA damage, leading to caspase-mediated apoptosis in glioblastoma cells. Importantly, therapeutic effects of PLK1 inhibitors were not influenced by MSH6 knockdown, indicating that their action is independent of MMR status of the cells. Systemic treatment with Volasertib potently inhibited tumor growth in an MMR-deficient, TMZ-resistant glioblastoma xenograft model. Further in vitro testing in established and patient-derived cell line panels revealed an association of PLK1 inhibitor efficacy with cellular Myc expression status. We found that cells with deregulated Myc are vulnerable to PLK1 inhibition, as Myc overexpression sensitizes, while its silencing desensitizes, glioblastoma cells to PLK1 inhibitors. This discovery is clinically relevant as glioma progression post-TMZ treatment is frequently accompanied by MYC genomic amplification and/or pathway activation. In conclusion, PLK inhibitor represents a novel therapeutic option for recurrent gliomas, including those TMZ-resistant from MMR deficiency. Genomic MYC alteration may serve as a biomarker for PLK inhibitor sensitivity, as Myc-driven tumors demonstrated pronounced responses.