Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application.
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DOI：
10.18632/oncotarget.14109
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发表时间：
2017-02-28
期刊：
影响因子：
--
通讯作者：
Giles FJ
中科院分区：
文献类型：
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作者：
Chae YK;Ranganath K;Hammerman PS;Vaklavas C;Mohindra N;Kalyan A;Matsangou M;Costa R;Carneiro B;Villaflor VM;Cristofanilli M;Giles FJ
成纤维细胞生长因子/成纤维细胞生长因子受体(成纤维细胞生长因子/成纤维细胞生长因子受体)是一种酪氨酸激酶信号通路，在胚胎发育、组织再生和血管生成等许多生物学过程中起着重要的作用。越来越多的证据表明，该途径通过基因扩增、激活突变或在不同组织的肿瘤中易位在肿瘤发生中发挥关键作用。随着多重测序技术的发展，FGFR异常的检测已经变得更加常见，并与癌细胞增殖、抗癌治疗的耐药性和新血管生成有关。在临床前研究中，抑制FGFR信号似乎很有希望，这表明靶向治疗的发展是一条临床感兴趣的途径。I期试验已经证明了一种可控的毒性特征。目前，有多种FGFR抑制剂在研究中，许多非选择性(多激酶)抑制剂显示出有限的临床反应。随着我们从第一代非选择性药物发展到第二代选择性FGFR抑制剂，很明显，FGFR异常在不同类型的癌症中表现不一致；因此，毫无疑问，有必要更深入地了解生物标记物的策略。这篇综述旨在巩固最近临床试验的数据，重点是选择性FGFR抑制剂。随着第二阶段临床试验的出现，应将注意力集中在患者选择上，因为这与预测治疗反应有关，克服毒性的可行方法，以及联合治疗的可能性。我们还将讨论未来几代FGFR抑制剂可能需要的品质，希望克服这些目前的障碍将加快这类新型药物的问世。
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.