Doddapaneni Ravi, Tao Wensi, Naranjo Andrea, Nikpoor Neda, Tse David T, Pelaez Daniel
Dr. Nasser Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Biomedical Engineering, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Oncotarget. 2019 Jan 11;10(4):480-493. doi: 10.18632/oncotarget.26558.
Identification of molecular targets is the first step in developing efficacious therapeutic strategies for tumors. A tumors' biological response to perturbagens yields important information on the molecular determinants for tumor growth. The aim of this study was to characterize the response of adenoid cystic carcinoma of the lacrimal gland (LGACC) to intra-arterial cytoreductive chemotherapy (IACC) in order to identify novel targets to enhance therapy. We performed high-throughput proteomic analysis on paired samples from pre-IACC diagnostic biopsies and post-IACC excised tumor samples from 6 LGACC patients. This proteomic analysis provides a comprehensive landscape of the cellular compartments contained within the excised tumors. Interestingly, we found a strong upregulation across the fibroblast growth factor (FGF) signaling pathway, with FGF receptor 1 (FGFR1) exhibiting a consistent and significant upregulation in all post-IACC samples. We thus evaluated the therapeutic efficacy of a novel FGFR1 selective inhibitor, AZD4547, in combination with cisplatin on LGACC cells in-vitro. The combination index (CI) value (<0.895) demonstrated synergistic effect of AZD4547 and cisplatin in inhibiting cell growth and viability (p<0.02), with a differential response seen in post-IACC cultures when compared to pre-IACC cultures. The combination approach showed synergy of the drugs in the migration assay. Western blot analysis indicated a significant upregulation of cleaved caspase-3 and downregulation the expression of FGFR1 (p<0.05) with the combination treatment as compared to either agent independently. Our findings demonstrate that FGFR1 inhibition potentiates the cytoreductive effects of cisplatin and suggest a potential therapeutic benefit of using AZD4547 in the management of LGACC.
识别分子靶点是开发有效的肿瘤治疗策略的第一步。肿瘤对干扰因素的生物学反应可产生有关肿瘤生长分子决定因素的重要信息。本研究的目的是表征泪腺腺样囊性癌（LGACC）对动脉内细胞减灭化疗（IACC）的反应，以确定增强治疗效果的新靶点。我们对6例LGACC患者IACC前诊断性活检的配对样本和IACC后切除的肿瘤样本进行了高通量蛋白质组分析。这种蛋白质组分析提供了切除肿瘤中所含细胞区室的全面概况。有趣的是，我们发现成纤维细胞生长因子（FGF）信号通路全面上调，FGF受体1（FGFR1）在所有IACC后样本中均呈现一致且显著的上调。因此，我们评估了新型FGFR1选择性抑制剂AZD4547与顺铂联合对LGACC细胞的体外治疗效果。联合指数（CI）值（<0.895）表明AZD4547和顺铂在抑制细胞生长和活力方面具有协同作用（p<0.02），与IACC前培养物相比，IACC后培养物呈现出不同的反应。联合用药方法在迁移试验中显示出药物的协同作用。蛋白质印迹分析表明，与单独使用任何一种药物相比，联合治疗可使裂解的半胱天冬酶-3显著上调，FGFR1表达下调（p<0.05）。我们的研究结果表明，抑制FGFR1可增强顺铂的细胞减灭作用，并提示使用AZD4547治疗LGACC具有潜在的益处。
