Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury
Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury
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DOI：
10.1158/1535-7163.mct-17-0324
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发表时间：
2018-03-01
影响因子：
5.7
通讯作者：
Isacchi, Antonella
中科院分区：
文献类型：
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作者：
Magnaghi, Paola;Salom, Barbara;Isacchi, Antonella
脊索瘤是一种罕见的骨肿瘤，目前尚无有效的治疗方法。这些肿瘤表达几种活化的酪氨酸激酶受体，这促使尝试用酪氨酸激酶抑制剂治疗患者。尽管在伊马替尼和索拉非尼的II期临床试验中观察到临床获益，偶尔也观察到EGFR抑制剂的临床获益，但迄今为止评价的治疗显示出适度的活性。为了确定对脉络膜患者具有直接治疗潜力的新药，我们收集了临床批准的药物和MET、PDGFR β和EGFR酪氨酸激酶的其他高级抑制剂，并评估了它们对一组脉络膜细胞系的抗增殖活性。脉络膜细胞系对MET和PDGFR β抑制剂无反应。U-CH 1和UM-Chor 1对所有EGFR抑制剂敏感，而其余细胞系通常对这些药物不敏感。阿法替尼是唯一一种在脉络膜组中具有活性的EGFR抑制剂。然后，我们研究了观察到的反应背后的分子机制，发现抗增殖IC（50）与阿法替尼促进EGFR和brachyury降解的独特能力相关，brachyury是一种胚胎转录因子，被认为是脉络膜炎的关键驱动因素。阿法替尼在体内U-CH 1、SF 8894、CF 322和CF 365脉络膜肿瘤模型中显示出强效抗肿瘤疗效。在分析的组中，EGFR磷酸化水平高、AXL和STK 33表达水平低与阿法替尼敏感性较高相关，值得作为潜在的缓解生物标志物进行进一步研究。这些数据支持在临床试验中使用阿法替尼，并为即将进行的阿法替尼治疗晚期脉络膜炎的欧洲II期研究提供了依据。(C)2017年AACR。
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFR beta, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFR beta inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC(50)s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models in vivo. In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma. (C) 2017 AACR.