Pilli Tania, Cantara Silvia, Marzocchi Carlotta, Pacini Furio, Prabhakar Bellur S, Castagna Maria Grazia
Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA.
Endocrine. 2020 Jan;67(1):117-123. doi: 10.1007/s12020-019-02028-2. Epub 2019 Aug 3.
Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206).
Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C).
C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model.
TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
间变性甲状腺癌（ATC）罕见但预后较差。肿瘤坏死因子相关凋亡诱导配体（TRAIL）可选择性诱导癌细胞凋亡；然而，耐药情况相当常见。我们研究的目的是评估TRAIL在体外和体内对ATC来源细胞系诱导凋亡的作用，以及与针对BRAF（维莫非尼）或Akt（MK - 2206）的酪氨酸激酶抑制剂（TKIs）联合使用的效果。
使用了四种ATC来源的细胞系：C643、CAL62、HTh7，其中HTh7具有RAS激活突变和PI3K拷贝数增加，以及8505C具有BRAF激活突变。细胞单独用TRAIL处理或与维莫非尼或MK - 2206联合处理。还在两种小鼠异种移植模型（HTh7和8505C）中评估了TRAIL单独或与TKIs联合使用的促凋亡作用。
C643、CAL62和HTh7细胞对TRAIL诱导的凋亡敏感，而8505C细胞耐药。在体外和体内，维莫非尼均能增加8505C细胞中TRAIL诱导的凋亡，与安慰剂相比，在8505C异种移植模型中导致肿瘤生长较慢，而MK - 2206在HTh7模型中对TRAIL治疗没有任何附加作用。
TRAIL是ATC中有前景的治疗药物，在耐药情况下维莫非尼可能是有效的辅助治疗方法。
