Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?
Receptor tyrosine kinases as druggable targets in glioblastoma: Do signaling pathways matter?
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DOI：
10.1093/noajnl/vdab133
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Xie Q
中科院分区：
文献类型：
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作者：
Qin A;Musket A;Musich PR;Schweitzer JB;Xie Q
胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，目前尚无有效的治疗方法。由于贝伐单抗被FDA批准用于治疗复发性GBM成人患者的血管内皮生长因子受体2 (VEGFR2)，靶向治疗受体酪氨酸激酶（RTKs）已成为GBM治疗的新途径。除VEGFR外，表皮生长因子受体（EGFR）、血小板衍生生长因子受体（PDGFR）、肝细胞生长因子受体（HGFR/MET）和成纤维细胞生长因子受体（FGFR）也是RTK的主要靶点。然而，临床II/III期试验的结果表明，大多数针对rtk的治疗方法，包括酪氨酸激酶抑制剂（TKIs）和中和抗体，无论是单独使用还是联合使用，都缺乏临床疗效。主要的挑战是揭示驱动GBM发生和进展的遗传RTK改变，以及阐明治疗耐药的机制。在这篇综述中，我们将讨论这5种常见靶向rtk的遗传改变，相关rtk靶向治疗的临床试验结果，以及耐药的潜在机制。我们预计，基于个体患者肿瘤内的遗传改变和治疗后产生治疗耐药性的机制，未来设计新的临床试验，采用联合策略，将实现持久的缓解，并改善GBM患者的预后。
Glioblastoma (GBM) is the most malignant primary brain tumor without effective therapies. Since bevacizumab was FDA approved for targeting vascular endothelial growth factor receptor 2 (VEGFR2) in adult patients with recurrent GBM, targeted therapy against receptor tyrosine kinases (RTKs) has become a new avenue for GBM therapeutics. In addition to VEGFR, the epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) are major RTK targets. However, results from clinical Phase II/III trials indicate that most RTK-targeting therapeutics including tyrosine kinase inhibitors (TKIs) and neutralizing antibodies lack clinical efficacy, either alone or in combination. The major challenge is to uncover the genetic RTK alterations driving GBM initiation and progression, as well as to elucidate the mechanisms toward therapeutic resistance. In this review, we will discuss the genetic alterations in these 5 commonly targeted RTKs, the clinical trial outcomes of the associated RTK-targeting therapeutics, and the potential mechanisms toward the resistance. We anticipate that future design of new clinical trials with combination strategies, based on the genetic alterations within an individual patient’s tumor and mechanisms contributing to therapeutic resistance after treatment, will achieve durable remissions and improve outcomes in GBM patients.