Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma.
Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma.
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DOI：
10.1186/s13046-020-01763-z
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发表时间：
2020-11-26
期刊：
影响因子：
--
通讯作者：
Tsang CM
中科院分区：
文献类型：
--
作者：
Xue Z;Lui VWY;Li Y;Jia L;You C;Li X;Piao W;Yuan H;Khong PL;Lo KW;Cheung LWT;Lee VHF;Lee AWM;Tsao SW;Tsang CM
最近的基因组分析显示，仅在约6%的鼻咽癌（NPC）患者中可检测到可药物分子靶点。然而，依赖于失调的CDK 4/6-cyclinD 1信号通路是NPC发病机制中的重要事件。在本研究中，我们的目的是通过使用新建立的原发性、复发性和转移性NPC的异种移植模型和细胞系，评估特异性CDK 4/6抑制剂palbociclib治疗NPC的疗效及其与其他化疗药物的相容性。我们在NPC细胞系和异种移植模型中评估了palbociclib单药治疗和palbociclib与顺铂或辛二酰异羟肟酸（SAHA）联合治疗的疗效。然后使用RNA测序来分析药物反应相关途径。建立了Palbociclib耐药NPC细胞系，以确定在出现Palbociclib耐药后顺铂作为二线治疗的潜在用途。我们进一步检查了Palbociclib治疗对顺铂耐药NPC细胞的疗效。在NPC细胞中，已证实palbociclib单药治疗可在体外诱导细胞周期停滞在G1期。Palbociclib单药治疗在所有六种体内测试的NPC肿瘤模型中也具有显着的抑制作用，肿瘤总体积和Ki-67增殖标志物表达的大幅减少表明了这一点。在NPC细胞中，同时给予palbociclib可减轻顺铂的体外细胞毒性作用。值得注意的是，palbociclib和SAHA同时治疗在体外和体内协同促进NPC细胞死亡。这种组合还通过诱导自噬相关的细胞死亡进一步抑制肿瘤生长。诱导palbociclib或顺铂耐药的NPC细胞系分别对顺铂或palbociclib治疗保持敏感。我们的研究结果为palbociclib作为NPC的替代疗法提供了重要支持，并提高了对palbociclib与其他化疗药物联合给药的有效时机的认识。我们的研究结果为palbociclib治疗NPC患者的首次人体临床试验设计提供了基础。补充信息随附于10.1186/s13046-020-01763-z。
Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6–cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC. We evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response–related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells. In NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro. Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo, as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro. Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo. This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively. Our study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC. Supplementary information accompanies this paper at 10.1186/s13046-020-01763-z.
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DOI：
10.1016/j.bbrc.2011.08.047
发表时间：
2011-09-16
影响因子：
3.1
作者：
Katsumi, Yoshiki;Iehara, Tomoko;Miyachi, Mitsuru;Yagyu, Shigeki;Tsubai-Shimizu, Satoko;Kikuchi, Ken;Tamura, Shinichi;Kuwahara, Yasumichi;Tsuchiya, Kunihiko;Kuroda, Hiroshi;Sugimoto, Tohru;Houghton, Peter J.;Hosoi, Hajime
通讯作者：
Hosoi, Hajime
影响因子：
5.7
作者：
Hui, Kwai Fung;Lam, Benjamin H. W.;Chiang, Alan K. S.
通讯作者：
Chiang, Alan K. S.
影响因子：
15.9
作者：
Cen, Ling;Carlson, Brett L.;Sarkaria, Jann N.
通讯作者：
Sarkaria, Jann N.
影响因子：
6.4
作者：
BUSSON, P;GANEM, G;TURSZ, T
通讯作者：
TURSZ, T
影响因子：
6.4
作者：
HUANG, DP;HO, JHC;LUI, M
通讯作者：
LUI, M