文章：

靶向FGFR信号在癌症中的进展和挑战

Advances and challenges in targeting FGFR signalling in cancer

原文发布日期：2017-03-17

DOI: 10.1038/nrc.2017.8

类型: Review Article

开放获取: 否

要点：

1. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in many developmental and physiological processes through regulation of cell survival and proliferation.
2. Deregulation of FGFR signalling is frequently observed in many types of cancer.
3. Oncogenic FGFR signalling can be deregulated by various mechanisms, such as gene amplification, activating mutations and chromosomal translocations, as well as abnormal FGF ligand-mediated signalling.
4. Downstream FGF signalling frequently activates the MAPK–ERK pathway, and in some contexts the PI3K–AKT and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling pathways.
5. Numerous targeted therapies, including small-molecule tyrosine kinase inhibitors (TKIs), FGFR-blocking antibodies and ligand traps, have been developed to attenuate FGFR signalling in cancer, with potent anti-proliferative effects reported in preclinical models.
6. Targeting FGFR in the clinic has had variable results, and identifying cancers that are addicted to the FGFR pathway will be crucial for successful targeting of FGFR in the clinic.
7. Off-target effects of multi-targeting TKIs and the toxicity of selective FGFR inhibitors are limiting factors for effective FGFR targeting. New-generation TKIs and anti-FGFR antibodies offer a promising strategy to overcome the lack of efficacy.
8. Delineating individual contributions of FGFR aberrations to specific cancers would aid better patient stratification and guide more effective treatment strategies to delay the emergence of drug resistance.

要点翻译：

1. 成纤维细胞生长因子（FGFs）及其受体（FGFRs）通过调控细胞存活与增殖，参与多种发育和生理过程。
2. FGFR信号通路的失调常见于多种癌症类型。
3. 致癌性FGFR信号可通过多种机制失控，例如基因扩增、激活突变、染色体易位以及异常的FGF配体介导信号传导。
4. 下游FGF信号通常会激活MAPK–ERK通路，在某些情况下也会激活PI3K–AKT和Janus激酶-信号转导与转录激活因子（JAK–STAT）信号通路。
5. 目前已有多种靶向疗法被开发用于抑制癌症中的FGFR信号，包括小分子酪氨酸激酶抑制剂（TKIs）、FGFR阻断抗体和配体陷阱，临床前研究报道其具有显著抗增殖效应。
6. 临床中靶向FGFR的治疗效果不一，识别FGFR通路依赖型癌症将成为成功实现临床靶向的关键。
7. 多靶点TKI的脱靶效应及选择性FGFR抑制剂的毒性是限制有效靶向的主要因素。新一代TKI和抗FGFR抗体为克服疗效不足提供了前景良好的策略。
8. 明确FGFR异常对特定癌症的个体化贡献，将有助于优化患者分层，并指导制定更有效的治疗策略以延缓耐药性出现。

英文摘要：

Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Deregulation of FGFR signalling is observed in a subset of many cancers, making activated FGFRs a highly promising potential therapeutic target supported by multiple preclinical studies. However, early-phase clinical trials have produced mixed results with FGFR-targeted cancer therapies, revealing substantial complexity to targeting aberrant FGFR signalling. In this Review, we discuss the increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting.

摘要翻译： 

成纤维细胞生长因子（FGF）及其受体（FGFR）调控众多细胞过程。在多种癌症的亚型中均可见FGFR信号失调，使得活化FGFR成为多个临床前研究支持的高度 promising 潜在治疗靶点。然而，早期临床试验针对FGFR的癌症靶向疗法结果不一，揭示了靶向异常FGFR信号的复杂性。本综述探讨对FGFR致癌激活不同机制差异的日益深入理解，以及决定FGFR靶向治疗反应与耐药的因素。

原文链接：

Advances and challenges in targeting FGFR signalling in cancer