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纤维母细胞生长因子受体1（FGFR1）扩增可见于约15%的雌激素受体（ER）阳性乳腺癌患者，可以引起抗雌激素治疗耐药。 2017年10月15日，美国癌症研究学会《临床癌症研究》正式发表范德堡大学、不勒斯腓特烈二世大学、费拉拉大学的研究报告，调查了FGFR1扩增引起ER阳性乳腺癌抗雌激素治疗耐药的机制，发现FGFR1与ERα可维持不依赖配体ER转录并引起ER阳性乳腺癌抗雌激素治疗耐药。 该研究利用术前接受来曲唑治疗患者的ER阳性肿瘤，进行Ki67免疫组化、FGFR1荧光原位杂交、RNA测序。使用FGFR1小分子干扰RNA或德立替尼（FGFR酪氨酸激酶抑制剂）对ER阳性且FGFR1扩增的乳腺癌细胞和患者来源异种移植物进行处理。研究终点为乳腺癌细胞和患者来源异种移植物的生长、通过免疫共沉淀和邻位连接检测的FGFR1和ERα、通过染色质免疫沉淀（ChIP）测序检测的ER基因组活性、通过逆转录聚合酶链反应（RT-PCR）检测的基因表达。 结果发现：
因此，这些数据表明，对于雌激素被剥夺的ER阳性且FGFR1扩增乳腺癌，ERα通路仍有活性，这些肿瘤对内分泌疗法耐药，应该成为ER和FGFR拮抗剂联合治疗的候选者。 Clin Cancer Res. 2017 Oct 15;23(20):6138-6150. Association of FGFR1 with ERα Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER+ Breast Cancer. Formisano L, Stauffer KM, Young CD, Bhola NE, Guerrero-Zotano AL, Jansen VM, Estrada MM, Hutchinson KE, Giltnane JM, Schwarz LJ, Lu Y, Balko JM, Deas O, Cairo S, Judde JG, Mayer IA, Sanders M, Dugger TC, Bianco R, Stricker T, Arteaga CL. Vanderbilt University Medical Center, Nashville, Tennessee; University of Naples Federico II, Naples, Italy; XenTech, Evry, France; University of Ferrara, Ferrara, Italy. PURPOSE: FGFR1 amplification occurs in approximately 15% of estrogen receptor-positive (ER+) human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer. EXPERIMENTAL DESIGN: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 IHC, FGFR1 FISH, and RNA sequencing (RNA-seq). ER+/FGFR1-amplified breast cancer cells, and patient-derived xenografts (PDX) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by coimmunoprecipitation and proximity ligation, ER genomic activity by ChIP sequencing, and gene expression by RT-PCR. RESULTS: ER+/FGFR1-amplified tumors in patients treated with letrozole maintained cell proliferation (Ki67). Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands expression in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ERα in tumor cell nuclei and regulated the transcription of ER-dependent genes. This association was inhibited by a kinase-dead FGFR1 mutant and by treatment with lucitanib. ChIP-seq analysis of estrogen-deprived ER+/FGFR1-amplified cells showed binding of FGFR1 and ERα to DNA. Treatment with fulvestrant and/or lucitanib reduced FGFR1 and ERα binding to DNA. RNA-seq data from FGFR1-amplified patients' tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified cells and PDXs was more potently inhibited by fulvestrant and lucitanib combined than each drug alone. CONCLUSIONS: These data suggest the ERα pathway remains active in estrogen-deprived ER+/FGFR1-amplified breast cancers. Therefore, these tumors are endocrine resistant and should be candidates for treatment with combinations of ER and FGFR antagonists. PMID: 28751448 DOI: 10.1158/1078-0432.CCR-17-1232
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