Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Invest New Drugs. 2018 Dec;36(6):961-969. doi: 10.1007/s10637-018-0575-z. Epub 2018 Mar 6.
Genomic studies have established a set of three core-signaling pathways, receptor tyrosine kinase (RTK), p53 and retinoblastoma (Rb) signaling pathways, contributing glioblastoma (GBM) and revealed that dysregulation of at least two pathways is required for GBM progression. In the present study, we investigate efficacy of combination of palbociclib, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and erlotinib, epidermal growth factor receptor (EGFR) inhibitor in GBM cell systems with different p53 status. Cell proliferation and colony formation assays showed that the combination treatment synergistically suppressed GBM cell proliferation. LN229 cells with mutant p53 and wild-type PTEN were more sensitive to the combination treatment. Further studies indicated that the synergetic anti-GBM effects were due to cell apoptosis induction and cell cycle arrest at G1 phase. Signaling examination indicated that levels of p-Rb and p-4E-BP1 significantly decreased by the combination treatment; however, Akt and MAPK signaling were differentially suppressed among the three GBM cell lines. Hence, our data demonstrate that palbociclib and erlotinib exert synergistic anti-GBM activity, providing pre-clinical evidence and a proof-ofconcept that usage of the combination of EGFR and CDK4/6 inhibitors for GBM treatment.
基因组研究确立了一组三个核心信号通路，即受体酪氨酸激酶（RTK）、p53 和视网膜母细胞瘤（Rb）信号通路，这些通路与胶质母细胞瘤（GBM）有关，并揭示了至少两条通路的失调是 GBM 进展所必需的。在本研究中，我们研究了 palbociclib（CDK4/6 抑制剂）和厄洛替尼（EGFR 抑制剂）联合治疗不同 p53 状态的 GBM 细胞系统的疗效。细胞增殖和集落形成实验表明，联合治疗协同抑制 GBM 细胞增殖。具有突变型 p53 和野生型 PTEN 的 LN229 细胞对联合治疗更敏感。进一步的研究表明，协同的抗 GBM 作用是由于细胞凋亡诱导和细胞周期阻滞在 G1 期。信号检测表明，联合治疗显著降低了 p-Rb 和 p-4E-BP1 的水平；然而，三种 GBM 细胞系中 Akt 和 MAPK 信号的抑制程度不同。因此，我们的数据表明，palbociclib 和厄洛替尼对 GBM 具有协同的抗活性，为 EGFR 和 CDK4/6 抑制剂联合治疗 GBM 提供了临床前证据和概念验证。
