Department of Neurology, University of Virginia, Charlottesville, Virginia.
Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
Neuro Oncol. 2018 Jan 22;20(2):192-202. doi: 10.1093/neuonc/nox119.
The mesenchymal phenotype in glioblastoma (GBM) and other cancers drives aggressiveness and treatment resistance, leading to therapeutic failure and recurrence of disease. Currently, there is no successful treatment option available against the mesenchymal phenotype.
We classified patient-derived GBM stem cell lines into 3 subtypes: proneural, mesenchymal, and other/classical. Each subtype's response to the inhibition of diacylglycerol kinase alpha (DGKα) was compared both in vitro and in vivo. RhoA activation, liposome binding, immunoblot, and kinase assays were utilized to elucidate the novel link between DGKα and geranylgeranyltransferase I (GGTase I).
Here we show that inhibition of DGKα with a small-molecule inhibitor, ritanserin, or RNA interference preferentially targets the mesenchymal subtype of GBM. We show that the mesenchymal phenotype creates the sensitivity to DGKα inhibition; shifting GBM cells from the proneural to the mesenchymal subtype increases ritanserin activity, with similar effects in epithelial-mesenchymal transition models of lung and pancreatic carcinoma. This enhanced sensitivity of mesenchymal cancer cells to ritanserin is through inhibition of GGTase I and downstream mediators previously associated with the mesenchymal cancer phenotype, including RhoA and nuclear factor-kappaB. DGKα inhibition is synergistic with both radiation and imatinib, a drug preferentially affecting proneural GBM.
Our findings demonstrate that a DGKα-GGTase I pathway can be targeted to combat the treatment-resistant mesenchymal cancer phenotype. Combining therapies with greater activity against each GBM subtype may represent a viable therapeutic option against GBM.
胶质母细胞瘤（GBM）和其他癌症中的间充质表型可导致侵袭性和治疗耐药性，从而导致治疗失败和疾病复发。目前，针对间充质表型尚无有效的治疗选择。
我们将患者来源的 GBM 干细胞系分为 3 种亚型：神经前体细胞型、间充质型和其他/经典型。比较了每种亚型对二酰基甘油激酶α（DGKα）抑制的体外和体内反应。利用 RhoA 激活、脂质体结合、免疫印迹和激酶测定来阐明 DGKα 与香叶基香叶基转移酶 I（GGTase I）之间的新联系。
我们在此表明，小分子抑制剂利坦色林或 RNA 干扰抑制 DGKα 可优先靶向 GBM 的间充质亚型。我们表明，间充质表型使 DGKα 抑制变得敏感；将 GBM 细胞从神经前体细胞型转变为间充质亚型会增加利坦色林的活性，在肺和胰腺癌上皮间质转化模型中也具有类似的作用。间充质癌细胞对利坦色林的这种敏感性增强是通过抑制 GGTase I 和以前与间充质癌症表型相关的下游介质，包括 RhoA 和核因子-κB 来实现的。DGKα 抑制与放疗和伊马替尼协同作用，伊马替尼是一种优先影响神经前体细胞型 GBM 的药物。
我们的研究结果表明，DGKα-GGTase I 途径可以作为针对治疗耐药性间充质癌症表型的靶点。针对每种 GBM 亚型具有更高活性的联合疗法可能是治疗 GBM 的可行治疗选择。
