Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma
Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma
复制标题
DOI：
10.15252/emmm.201809081
复制
发表时间：
2019-02-01
影响因子：
11.1
通讯作者：
Aplin, Andrew E.
中科院分区：
文献类型：
--
作者：
Chua, Vivian;Orloff, Marlana;Aplin, Andrew E.
转录程序的改变促进肿瘤的发展和进展，并且可被溴结构域和末端外（BET）蛋白抑制剂靶向。然而，在一项在实体癌患者中测试新型BET抑制剂PLX51107的多中心临床试验中，葡萄膜黑色素瘤（UM）患者的肝转移在治疗后迅速进展。UM对BET抑制剂的耐药机制尚不清楚。我们发现，成纤维细胞生长因子2（FGF2）救出UM细胞从BET抑制剂的生长抑制，FGF受体（FGFR）抑制剂和FGF2的影响是可逆的。BET抑制剂还增加了UM细胞系和患者肿瘤样本中的FGFR蛋白表达。肝星状细胞（HSC）分泌FGF2，HSC条件培养基提供UM细胞对BET抑制剂的抗性。PLX51107在体内无效，但FGFR抑制剂AZD 4547和PLX51107的组合显著抑制了由皮下接种具有HSC的UM细胞形成的异种移植UM肿瘤的生长，并且原位在肝脏中。这些结果表明，需要共靶向FGFR信号传导以增加转移性UM对BET抑制剂的反应。
Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC-conditioned medium provided resistance of UM cells to BET inhibitors. PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver. These results suggest that co-targeting of FGFR signaling is required to increase the responses of metastatic UM to BET inhibitors.