Clinical Cancer Research





① 采用参与NCT00651976、术前接受来曲唑治疗的ER+患者的肿瘤组织及细胞株;② 来曲唑治疗的ER+/FGFR1扩增肿瘤仍保持细胞增殖,富含雌激素应答和E2F靶基因,总的和核内FGFR1及FGF配体表达增加;③ FGFR1的无激酶活性突变和lucitanib处理可抑制FGFR1与肿瘤细胞核ERα的协同作用;④ 氟维司群和/或lucitanib的处理减少FGFR1和ERα与DNA的结合,且联合用药强于单药;⑤ 剥夺雌激素的ER+/FGFR1扩增的乳腺癌中,ERα通路保持活化,对内分泌治疗耐药。

氟维司群 耐药 乳腺癌


Association of FGFR1 with ERαmaintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer


Abstract & Authors展开

FGFR1 amplification occurs in ~15% of ER+ human breast cancers. We investigated mechanisms by which FGFR1 amplification confers antiestrogen resistance to ER+ breast cancer.<br /><br />Experimental Design: ER+ tumors from patients treated with letrozole before surgery were subjected to Ki67 immunohistochemistry, FGFR1 FISH, and RNA-sequencing. ER+/FGFR1 amplified breast cancer cells and patient-derived xenografts (PDXs) were treated with FGFR1 siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints were cell/xenograft growth, FGFR1/ERα association by co-immunoprecipitation and proximity ligation, ER genomic activity by ChIP-sequencing, and gene expression by RT-PCR.<br /><br />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.<br /><br />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.

All Authors:
Luigi Formisano,Kimberly Mae Stauffer,Christian D Young,Neil E Bhola,Angel L Guerrero-Zotano,Valerie M Jansen,Monica M Estrada,Katherine E Hutchinson,Jennifer M Giltnane,Luis J Schwarz,Yao Lu,Justin M Balko,Olivier Deas,Stefano Cairo,Jean-Gabriel Judde,Ingrid A Mayer,Melinda Sanders,Teresa C Dugger,Roberto Bianco,Thomas Stricker,Carlos L Arteaga

First Authors:
Luigi Formisano

Thomas Stricker,Carlos L Arteaga