Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma.
Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma.
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DOI：
10.1136/gutjnl-2016-312268
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发表时间：
2017-07
期刊：
影响因子：
24.5
通讯作者：
Lujambio A
中科院分区：
文献类型：
--
作者：
Bollard J;Miguela V;Ruiz de Galarreta M;Venkatesh A;Bian CB;Roberto MP;Tovar V;Sia D;Molina-Sánchez P;Nguyen CB;Nakagawa S;Llovet JM;Hoshida Y;Lujambio A
晚期肝细胞癌是一种致命的恶性肿瘤，治疗方法有限。Palbociclib是一种耐受性良好的选择性CDK4/6抑制剂，在治疗视网膜母细胞瘤(RB1)阳性乳腺癌方面显示出良好的效果。Rb1在肝细胞癌中很少发生突变，提示Palbociclib可能用于肝细胞癌的治疗。在这里，我们提供了一个全面的特征，在多种肝细胞癌的临床前模型中帕博西利的疗效。在一组人肝癌细胞系、体外人肝癌标本、基因工程小鼠肝癌模型和体内人肝癌异种移植瘤中，研究了帕波西利对细胞增殖、细胞衰老和细胞死亡的影响。通过蛋白质和基因表达分析，在人肝癌细胞系和人肝细胞癌标本中评估了对帕博西利的内在和获得性耐药机制。Palbociclib通过促进可逆的细胞周期停滞抑制人肝癌细胞系的细胞增殖。对帕博西利的内在和获得性耐药性是由RB1的缺失决定的。在30%的肝细胞癌样本中发现了‘RB1功能丧失’的特征。Palbociclib单独或与索拉非尼合用，这是治疗肝癌的标准药物，会损害体内肿瘤的生长并显著提高存活率。Palbociclib在肝细胞癌的临床前模型中显示了令人鼓舞的结果，并代表了一种治疗肝细胞癌的新策略，单独或特别是与索拉非尼联合治疗。Palbociclib可能使RB1熟练的肿瘤患者受益，这些肿瘤占所有肝细胞癌患者的70%。
Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of ‘RB1 loss of function’ was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
11.5
作者：
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Schwartz, Gary K.
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.
影响因子：
2.7
作者：
Chen B;Sirota M;Fan-Minogue H;Hadley D;Butte AJ
通讯作者：
Butte AJ