Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell Syst. 2019 Jul 24;9(1):74-92.e8. doi: 10.1016/j.cels.2019.05.009. Epub 2019 Jul 10.
There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to β-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.
目前迫切需要新的抗有丝分裂药物组合来针对癌症特有的脆弱性。基于我们在有丝分裂期癌细胞中发现的生物分子氧化升高的发现，我们将 Plk1 抑制剂与 TH588（一种可防止氧化核苷酸三磷酸解毒的 MTH1 抑制剂）联合使用。该组合对癌细胞具有强大的协同杀伤作用，但对正常细胞没有杀伤作用，令人惊讶的是，这种协同作用与 MTH1 无关。为了剖析潜在的协同作用机制，我们开发了 VISAGE，这是一种将实验协同作用定量与基于计算途径的基因表达分析相结合的策略。VISAGE 预测，并且我们通过实验证实，这种协同组合治疗靶向有丝分裂纺锤体。具体来说，TH588 与 β-微管蛋白结合会损害微管组装，当与 Plk1 阻断结合时，会协同破坏有丝分裂染色体在纺锤体中部的定位。这些发现确定了一种癌症特有的有丝分裂脆弱性，可使用 Plk1 抑制剂与微管破坏剂靶向治疗，并且突出了 VISAGE 方法阐明药物协同作用的分子机制的普遍适用性。
