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, PDGFRβ, 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 PDGFRβ 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 IC50s 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. Mol Cancer Ther; 17(3); 603–13. ©2017 AACR.

中文翻译：

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阿法替尼是一种新的脊索瘤治疗方法，具有针对 EGFR 和 Brachyury 的独特能力

脊索瘤是罕见的骨肿瘤，尚无批准的治疗方法。这些肿瘤表达几种活化的酪氨酸激酶受体，这促使人们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益处，偶尔也观察到 EGFR 抑制剂，但迄今为止评估的治疗显示出适度的活性。为了确定对脊索瘤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其他 MET、PDGFRβ 和 EGFR 酪氨酸激酶的高级抑制剂，并评估了它们对一组脊索瘤细胞系的抗增殖活性。脊索瘤细胞系对 MET 和 PDGFRβ 抑制剂没有反应。U-CH1 和 UM-Chor1 对所有 EGFR 抑制剂敏感，而其余的细胞系通常对这些药物不敏感。阿法替尼是唯一在脊索瘤组中具有活性的 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 IC50 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，被认为是脊索瘤的关键驱动因素。阿法替尼在体内 U-CH1、SF8894、CF322 和 CF365 脊索瘤肿瘤模型中显示出强大的抗肿瘤功效。在分析的小组中，高 EGFR 磷酸化和低 AXL 和 STK33 表达与对阿法替尼的更高敏感性相关，值得进一步研究作为潜在的反应生物标志物。这些数据支持在临床试验中使用阿法替尼，并为即将进行的关于阿法替尼治疗晚期脊索瘤的欧洲 II 期研究提供依据。摩尔癌症治疗; 17(3); 603-13。©2017 AACR。