Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.
Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.
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DOI：
10.1007/s00262-020-02609-5
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Pan CX
中科院分区：
文献类型：
--
作者：
Long Q;Ma AH;Zhang H;Cao Z;Xia R;Lin TY;Sonpavde GP;de Vere White R;Guo J;Pan CX
CDK4/6 通路的扰动在晚期膀胱癌中经常观察到。我们研究了单独靶向该通路或与化疗或免疫疗法联合作为膀胱癌治疗方法的潜力。首先使用癌症基因组图谱 (TCGA) 数据库分析了膀胱癌中 CDK4/6 通路的遗传改变，并在我们的膀胱癌患者来源的肿瘤异种移植物 (PDX) 中进行了验证。使用 CDK4/6 抑制剂 Palbociclib 治疗膀胱癌细胞系和携带 CDK4/6 通路扰动 PDX 的小鼠，以确定其抗癌活性和潜在机制。采用组合指数法评估哌柏西利和吉西他滨药物间相互作用。使用同基因小鼠膀胱癌模型 BBN963 来评估 palbociclib 是否可以增强抗 PD-1 免疫治疗。在 413 个膀胱癌样本中，79.2% 存在 CDK4/6 通路的微扰。 Palbociclib 诱导 G0/G1 细胞周期停滞，但体外细胞凋亡最小。在携带 PDX 的小鼠中，与仅使用载体的对照组相比，palbociclib 治疗可减少肿瘤生长并将生存期从 14 天延长至 32 天 (p=0.0001)。 Palbociclib 治疗与细胞系和 PDX 中 Rb 磷酸化的降低相关。 Palbociclib 和吉西他滨在体外 (CI > 3) 和体内表现出拮抗细胞毒性，但在同基因小鼠模型中显着增强抗 PD1 免疫疗法的治疗效果并诱导 CD8+ T 淋巴细胞浸润。 CDK4/6通路作为膀胱癌治疗的潜在靶点是可行的，特别是与免疫疗法相结合。 CDK4/6 抑制剂不应与吉西他滨联合使用。
Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer The genetic alterations of the CDK4/6 pathway in bladder cancer was first analyzed with The Cancer Genome Atlas (TCGA) database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anti-cancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD-1 immunotherapy. Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 days to 32 days compared to vehicle only controls (p=0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI >3) and in vivo, but significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.
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影响因子：
11.5
作者：
Dickson, Mark A.
通讯作者：
Dickson, Mark A.
影响因子：
8
作者：
Dean, J. L.;Thangavel, C.;Knudsen, E. S.
通讯作者：
Knudsen, E. S.
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：
11.2
作者：
Michaud K;Solomon DA;Oermann E;Kim JS;Zhong WZ;Prados MD;Ozawa T;James CD;Waldman T
通讯作者：
Waldman T
影响因子：
45.3
作者：
De Santis, Maria;Bellmunt, Joaquim;Sylvester, Richard
通讯作者：
Sylvester, Richard