AZD8055 enhances in vivo efficacy of afatinib in chordomas.
AZD8055 enhances in vivo efficacy of afatinib in chordomas.
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AZD 8055增强阿法替尼在脊索瘤中的体内疗效。
DOI：
10.1002/path.5739
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发表时间：
2021-09
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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脊索瘤是发生在颅底、活动脊柱和骶尾部区域的原发性骨肿瘤，影响所有年龄段的患者。目前，还没有批准用于脊索瘤患者的药物。在这里，我们评估了针对脊索瘤致癌途径的小分子抑制剂作为单一药物和联合用药的抗肿瘤功效，以确定具有最大转化潜力的新治疗方法。针对脊索瘤患者来源的异种移植（PDX）模型在体内筛选了一组小分子化合物，并使用脊索瘤细胞系和异种移植模型进一步评估了潜在的协同组合。在测试的药物中，EGFR抑制剂（BIBX 1382、厄洛替尼和阿法替尼）、c-MET（克唑替尼）和mTOR（AZD8055）在体内显着抑制肿瘤生长，但不诱导肿瘤消退。使用厄洛替尼和克唑替尼共同抑制 EGFR 和 c-MET 可协同降低脊索瘤细胞系中的细胞活力，但不会导致体内活性增强。使用阿法替尼和 AZD8055 共同抑制 EGFR 和 mTOR 通路可协同降低脊索瘤细胞系的细胞活力。重要的是，这种双重抑制完全抑制了体内肿瘤的生长，显示出改善的肿瘤控制。总之，这些数据表明 EGFR、c-MET 和 mTOR 通路的单独抑制剂在体外和体内均可抑制脊索瘤生长。在几种临床前模型中，mTOR 抑制增加了 EGFR 抑制对脊索瘤生长的功效。从我们的研究中获得的见解可能为脊索瘤患者提供一种新颖的联合治疗策略。
Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma.
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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