Combined BRAF(V600E)- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer.
Combined BRAF(V600E)- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer.
复制标题
DOI：
10.18632/oncotarget.2130
复制
发表时间：
2014-06-30
期刊：
影响因子：
--
通讯作者：
Parangi S
中科院分区：
文献类型：
--
作者：
Vanden Borre P;Gunda V;McFadden DG;Sadow PM;Varmeh S;Bernasconi M;Parangi S
未变性（ATC）和难治性甲状腺乳头状癌（PTC）缺乏有效的治疗方法。抑制致癌的 BRAF 或 SRC 在甲状腺癌小鼠模型中具有显着的抗肿瘤作用，然而，这两种药物都不会诱导显着的细胞凋亡。在这里，我们报告 SRC 抑制剂达沙替尼进一步使 BRAFV600E 阳性甲状腺癌细胞对 BRAFV600E 抑制剂 PLX4720 敏感。 PLX4720 和达沙替尼联合治疗可协同抑制 PTC 和 ATC 细胞的增殖并减少迁移。尽管 PLX4720 并未在甲状腺癌细胞中诱导强烈的细胞凋亡，但与达沙替尼联合治疗却在 6 个细胞系中的 4 个细胞系中诱导了细胞凋亡。在免疫功能正常的 ATC 原位小鼠模型中，与单独使用 PLX4720 治疗相比，PLX4720 和达沙替尼联合治疗显着缩小了肿瘤体积。 PLX4720 治疗增加了免疫细胞浸润，并且在用 PLX4720 和达沙替尼治疗的小鼠中维持了这种效果。此外，相对于对照或单独治疗，联合治疗显着增加体内 caspase 3 裂解。总之，在 ATC 临床前模型中，PLX4720 和达沙替尼联合治疗可诱导细胞凋亡、增加免疫细胞浸润并减少肿瘤体积，表明 FDA 批准的这些药物的联合治疗可能具有治疗 ATC 或难治性 PTC 患者的潜力。
Anaplastic (ATC) and refractory papillary thyroid cancer (PTC) lack effective treatments. Inhibition of either oncogenic BRAF or SRC has marked anti-tumor effects in mouse models of thyroid cancer, however, neither drug induces notable apoptosis. Here we report that the SRC-inhibitor dasatinib further sensitizes BRAFV600E-positive thyroid cancer cells to the BRAFV600E-inhibitor PLX4720. Combined treatment with PLX4720 and dasatinib synergistically inhibited proliferation and reduced migration in PTC and ATC cells. Whereas PLX4720 did not induce robust apoptosis in thyroid cancer cells, combined treatment with dasatinib induced apoptosis in 4 of 6 lines. In an immunocompetent orthotopic mouse model of ATC, combined PLX4720 and dasatinib treatment significantly reduced tumor volume relative to PLX4720 treatment alone. Immune cell infiltration was increased by PLX4720 treatment and this effect was maintained in mice treated with both PLX4720 and dasatinib. Further, combined treatment significantly increased caspase 3 cleavage in vivo relative to control or either treatment alone. In conclusion, combined PLX4720 and dasatinib treatment induces apoptosis, increases immune cell infiltration and reduces tumor volume in a preclinical model of ATC, suggesting that the combination of these FDA-approved drugs may have potential for the treatment of patients with ATC or refractory PTC.