Neratinib augments the lethality of [regorafenib + sildenafil].
Neratinib augments the lethality of [regorafenib + sildenafil].
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DOI：
10.1002/jcp.27276
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发表时间：
2019-04
影响因子：
5.6
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Booth L;Roberts JL;Rais R;Cutler RE Jr;Diala I;Lalani AS;Hancock JF;Poklepovic A;Dent P
瑞戈非尼被批准用于治疗结直肠癌和肝细胞癌。在试验NCT 02466802中，我们发现瑞戈非尼可以安全地与PDE 5抑制剂西地那非联合治疗晚期实体瘤患者。本研究确定了获批的ERBB 1/2/4和RAS下调药物来那替尼是否可增强[瑞格非尼+西地那非]的致死率。来那替尼在结肠癌细胞中以大于相加的方式增强[瑞格非尼+西地那非]致死率。该药物组合降低了突变型K-RAS和多种组蛋白脱乙酰酶蛋白的表达，这需要自噬体形成。它导致GFP或RFP标记形式的K-RAS V12定位到大的细胞内囊泡中。与[瑞戈非尼+西地那非]相比，三种药物联合给药导致ATM-AMPK-ULK-1通路的激活程度更高、时间更长，并导致mTOR、AKT和p70 S6 K的抑制程度更高、失活时间更长。来那替尼引起的约70%的致死率增强需要ATM-AMPK信号传导，而Beclin 1、ATG 5、FADD和CD 95的敲低完全阻止了致死作用的增强。细胞暴露于[瑞戈非尼+西地那非]降低了检查点免疫治疗生物标志物PD-L1、ODC和IDO-1的表达，并增加了MHCA的表达，这也需要自噬体形成。特定HDAC蛋白的敲低概括了使用化学试剂观察到的效果。在体内，使用小鼠癌症模型，来那替尼显著增强了[瑞格非尼+西地那非]的抗肿瘤疗效。我们的数据支持进行一项新的三种药物I期试验，联合使用瑞戈非尼、西地那非和来那替尼。
Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802 we have discovered that regorafenib can be safely combined with the PDE5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS down-regulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase proteins, that required autophagosome formation. It caused GFP or RFP-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared to [regorafenib + sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mTOR, AKT and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ATM-AMPK signaling whereas knock down of Beclin1, ATG5, FADD and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers PD-L1, ODC and IDO-1 and increased the expression of MHCA, which also required autophagosome formation. Knock down of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the anti-tumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug phase I trial combining regorafenib, sildenafil and neratinib.
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影响因子：
--
作者：
Booth L;Roberts JL;Poklepovic A;Avogadri-Connors F;Cutler RE;Lalani AS;Dent P
通讯作者：
Dent P
影响因子：
5.5
作者：
Zhang, Quan-Jiang;McMillin, Shawna L.;Symons, J. David
通讯作者：
Symons, J. David
影响因子：
--
作者：
Booth L;Albers T;Roberts JL;Tavallai M;Poklepovic A;Lebedyeva IO;Dent P
通讯作者：
Dent P
影响因子：
64.8
作者：
DENT, P;LAVOINNE, A;COHEN, P
通讯作者：
COHEN, P
癌症的分子起源：结直肠癌的分子基础。
DOI：
10.1056/nejmra0804588
发表时间：
2009-12-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Markowitz SD;Bertagnolli MM
通讯作者：
Bertagnolli MM