■表皮生长因子受体(EGFR)的异常表达和激活导致批准了几种形式的EGFR抑制剂用于治疗患有多种上皮癌的患者。然而,尚未批准EGFR抑制剂用于治疗脑癌患者,这表明在某些患者中,仅靶向EGFR可能是不够的。
■在这项研究中,我们调查了EGFR家族所有成员的作用,其他生长因子受体,细胞周期蛋白,和下游细胞信号通路(例如,丝裂原活化蛋白激酶(MAPK),丝氨酸/苏氨酸蛋白激酶(AKT),信号转导和转录激活因子(STAT3),Src,Abelson鼠白血病病毒癌基因同源物(Abl))对一组人脑癌细胞系(HBCCL)的生长。与两种细胞毒性药物相比,我们检查了HBCCL对17种靶向药物治疗的生长反应。
■在目标特工中,不可逆的泛人表皮生长因子受体(HER)抑制剂neratinib和afatinib在抑制所有HBCCL的生长方面比厄洛替尼和拉帕替尼更有效,细胞周期蛋白依赖性激酶(CDK)1/2/5/9抑制剂dinaciclib是最有效的靶向药物。我们发现用Src/Abl/c-kit抑制剂达沙替尼治疗,信号转导和转录激活因子(STAT3)抑制剂stattic,Abl/血小板衍生生长因子受体(PDGFR)α/血管内皮生长因子(VEGFR)2/成纤维细胞生长因子受体(FGFR)1抑制剂普纳替尼,原肌球蛋白受体激酶(TRK)/ROS原癌基因1受体酪氨酸激酶(ROS)/间变性淋巴瘤激酶(ALK)抑制剂entrectinib,也抑制了所有HBCCL的生长。有趣的是,当以较慢的速率增殖时,这些药物对抑制HBCCL的生长更有效.除了抑制HBCCLs的增殖,用neratinib治疗,dinaciclib,达沙替尼,stattic和trametinib抑制脑肿瘤细胞系A172的迁移。
■值得注意的是,我们发现,奈拉替尼联合palbociclib(CDK4/6抑制剂)治疗,或miransertib(AKT1/2/3抑制剂)导致所有HBCCL的协同生长抑制。我们的结果支持,将neratinib等药物与palbociclib或miransertib联合使用可能具有治疗脑癌的潜力,值得进一步研究。
UNASSIGNED: Aberrant expression and activation of epidermal growth factor receptor (EGFR) resulted in approval of several forms of EGFR inhibitors in the treatment of patients with a wide range of epithelial cancers. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain cancer, indicating that targeting EGFR alone may not be sufficient in some patients.
UNASSIGNED: In this study, we investigated the role of all members of the EGFR family, other growth factor receptors, cell-cycle proteins, and downstream cell signaling pathways (e.g., mitogen-activated protein kinase (MAPK), serine/threonine protein kinase (AKT), signal transducer and activator of transcription (STAT3), Src, Abelson murine leukemia viral oncogene homolog (Abl)) on the growth of a panel of human brain cancer cell lines (HBCCLs). We examined the growth response of HBCCLs to treatment with 17 targeted agents compared to two cytotoxic drugs.
UNASSIGNED: Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor
dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib,
dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line A172.
UNASSIGNED: Notably, we found that treatment with neratinib in combination with palbociclib (CDK4/6 inhibitor), or miransertib (AKT1/2/3 inhibitor) resulted in synergistic growth inhibition of all HBCCLs. Our results support that repurposing drugs like neratinib in combination with the palbociclib or miransertib may be of therapeutic potential in brain cancer and warrants further investigations.