Katoh Masaru
Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan.
Int J Mol Med. 2016 Jul;38(1):3-15. doi: 10.3892/ijmm.2016.2620. Epub 2016 May 31.
Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients.
成纤维细胞生长因子（FGF）2、FGF4、FGF7和FGF20是典型的旁分泌FGF，它们与硫酸乙酰肝素蛋白聚糖和成纤维细胞生长因子受体（FGFR）结合，而FGF19、FGF21和FGF23是与Klotho和FGFR结合的内分泌FGF。FGFR1在乳腺癌和肺癌中相对频繁地扩增和过表达，FGFR2在胃癌中如此。骨髓增殖性肿瘤中的BCR - FGFR1、CNTRL - FGFR1、CUX1 - FGFR1、FGFR1OP - FGFR1、MYO18A - FGFR1和ZMYM2 - FGFR1融合蛋白是非受体型FGFR激酶，而实体瘤中的FGFR1 - TACC1、FGFR2 - AFF3、FGFR2 - BICC1、FGFR2 - PPHLN1、FGFR3 - BAIAP2L1和FGFR3 - TACC3融合蛋白是具有C末端改变的跨膜型FGFR。AZD4547、BGJ398（英菲格拉替尼）、Debio - 1347和多韦替尼是FGFR1/2/3抑制剂；BLU9931是一种选择性FGFR4抑制剂；FIIN - 2、JNJ - 42756493、LY2874455和波纳替尼是泛FGFR抑制剂。AZD4547、多韦替尼和波纳替尼是靶向FGFR、集落刺激因子1受体（CSF1R）、血管内皮生长因子（VEGF）R2等的多激酶抑制剂。肿瘤微环境由癌细胞和基质/免疫细胞组成，如癌症相关成纤维细胞（CAF）、内皮细胞、M2型肿瘤相关巨噬细胞（M2 - TAM）、髓源性抑制细胞（MDSC）和调节性T细胞。FGFR抑制剂直接对癌细胞产生抗肿瘤作用，也通过阻断旁分泌信号间接发挥作用。FGF和CSF1或VEGF信号的双重抑制有望通过靶向肿瘤微环境中的免疫逃逸和血管生成来增强抗肿瘤作用。使用酪氨酸激酶抑制剂（FGFR或CSF1R抑制剂）和免疫检查点阻滞剂（抗PD - 1或抗CTLA - 4单克隆抗体）的联合治疗可能是癌症患者的一个有前景的选择。FGF19 - FGFR4信号的抑制与肝毒性风险相关，而FGF23 - FGFR4信号的激活与心脏毒性风险相关。内分泌FGF信号影响使用FGFR抑制剂的癌症患者的病理生理学。全基因组测序对于检测FGFR基因的启动子/增强子改变以及导致FGFR过表达的其他基因的罕见改变是必要的。为了在老龄化社会维持医疗保健系统，在为癌症患者实施基于基因组的精准医学之前，应进行以无病生存期和总医疗成本为重点的效益成本分析。
