The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.
The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.
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DOI：
10.18632/oncotarget.14829
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发表时间：
2017-03-07
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影响因子：
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通讯作者：
Dent P
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作者：
Booth L;Roberts JL;Sander C;Lee J;Kirkwood JM;Poklepovic A;Dent P
研究集中在组蛋白去乙酰化酶（HDAC）抑制剂AR 42对活化的B-RAF黑色素瘤细胞的杀伤作用。与其他肿瘤细胞系相比，PDX黑色素瘤分离株对AR 42诱导的杀伤显著更敏感。AR 42和多激酶抑制剂帕唑帕尼相互作用激活：eIF 2 α-Beclin 1通路导致自噬体形成; eIF 2 α-DR 4/DR 5/CD 95通路;以及eIF 2 α依赖性c-FLIP-s、MCL-1和BCL-XL表达降低。AR 42没有改变基础伴侣活性，但增加了帕唑帕尼抑制HSP 90、HSP 70和GRP 78的能力。AR 42和帕唑帕尼导致HSP 90/HSP 70从RAF-1和B-RAF解离，导致“RAF”表达减少。联合用药激活了DNA损伤-ATM-AMPK通路，该通路与以下因素相关：NFκB激活; mTOR S2448和ULK-1 S757磷酸化减少; ULK-1 S317和ATG 13 S318磷酸化增加。PERK、eIF 2 α、Beclin 1、ATG 5或AMPKα的敲低，或IκB S32 A S36 A、ca-mTOR或TRX的表达降低细胞杀伤。AR 42通过溶酶体降解降低HDAC 2/5/6/10/11的蛋白质表达。在体内，达拉非尼/曲美替尼抗性黑色素瘤细胞暴露于AR 42帕唑帕尼组合3天减少了肿瘤生长，并将存活期从25天提高到40天。通过治疗适应的肿瘤细胞显示出升高的HGF表达，c-MET抑制剂克唑替尼增强了AR 42帕唑帕尼在这个进化的耐药群体中的致死率。
Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2α–Beclin1 pathway causing autophagosome formation; an eIF2α–DR4/DR5/CD95 pathway; and an eIF2α-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78. AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced ‘RAF’ expression. The drug combination activated a DNA-damage-ATM-AMPK pathway that was associated with: NFκB activation; reduced mTOR S2448 and ULK-1 S757 phosphorylation; and increased ULK-1 S317 and ATG13 S318 phosphorylation. Knock down of PERK, eIF2α, Beclin1, ATG5 or AMPKα, or expression of IκB S32A S36A, ca-mTOR or TRX, reduced cell killing. AR42, via lysosomal degradation, reduced the protein expression of HDACs 2/5/6/10/11. In vivo, a 3-day exposure of dabrafenib/trametinib resistant melanoma cells to the AR42 pazopanib combination reduced tumor growth and enhanced survival from ∼25 to ∼40 days. Tumor cells that had adapted through therapy exhibited elevated HGF expression and the c-MET inhibitor crizotinib enhanced AR42 pazopanib lethality in this evolved drug-resistant population.