Palbociclib-based high-throughput combination drug screening identifies synergistic therapeutic options in HPV-negative head and neck squamous cell carcinoma.
Palbociclib-based high-throughput combination drug screening identifies synergistic therapeutic options in HPV-negative head and neck squamous cell carcinoma.
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DOI：
10.1186/s12916-022-02373-6
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发表时间：
2022-05-12
期刊：
影响因子：
9.3
通讯作者：
Zhou, Rong
中科院分区：
文献类型：
--
作者：
Gu, Ziyue;Shi, Chaoji;Li, Jiayi;Han, Yong;Sun, Bao;Zhang, Wuchang;Wu, Jing;Zhou, Guoyu;Ye, Weimin;Li, Jiang;Zhang, Zhiyuan;Zhou, Rong
在人乳头瘤病毒阴性（HPVneg）的头颈部鳞状细胞癌（HNSCC）中普遍观察到细胞周期途径的失调。尽管palbociclib是一个有吸引力的靶点，但在HPV阴性HNSCC患者中，palbociclib单药治疗或与含铂化疗或西妥昔单抗联合治疗时，CDK 4/6抑制作用显示出适度或相互矛盾的结果。因此，增加palbociclib在HPV阴性HNSCC中疗效的创新药物将受到欢迎。以组合矩阵形式筛选了162种FDA批准的研究药物，并在更广泛的HPV阴性HNSCC细胞系中验证了最佳组合。通过转录谱分析探讨药物协同作用的分子机制。最后，在一组遗传多样性HPV阴性HNSCC细胞系和患者源性异种移植模型中，评价了最有效的基于palbociclib的药物组合，并与palbociclib+西妥昔单抗或顺铂进行了比较。Palbociclib单药治疗HPVneg HNSCC的疗效有限。高通量联合药物筛选提供了全面的基于palbociclib的药物相互作用数据集，而当palbociclib与多种药物（包括PI 3 K、EGFR和MEK途径抑制剂）联合使用时，观察到了显着的协同效应。当与palbociclib联合使用时，PI 3 K通路抑制剂可显著降低HPVneg HNSCC细胞系的细胞增殖并诱导细胞周期停滞，而alpelisib（一种PI 3 K α抑制剂）已被证明在携带PIK 3CA改变的HNSCC中显示出最有效的协同作用，尤其是更高的疗效。值得注意的是，与顺铂和西妥昔单抗相比，alpelisib在更广泛的细胞系中发挥了更强的协同作用。从机制上讲，alpelisib和西妥昔单抗（而非顺铂）可减弱palbociclib诱导的RRM 2依赖性上皮间质转化（EMT）。随后，具有不同遗传背景的PDX模型进一步验证了palbociclib + alpelisib在携带PIK 3CA扩增的模型中具有显著的协同效应。本研究提供了与CDK 4/6抑制相关的系统性联合效应的见解，并支持在PIK 3CA改变的HPV阴性HNSCC患者中进一步启动使用palbociclib + alpelisib联合治疗的临床试验。在线版本包含补充材料，可通过10.1186/s12916-022-02373-6获得。
Deregulation of cell-cycle pathway is ubiquitously observed in human papillomavirus negative (HPVneg) head and neck squamous cell carcinoma (HNSCC). Despite being an attractive target, CDK4/6 inhibition using palbociclib showed modest or conflicting results as monotherapy or in combination with platinum-based chemotherapy or cetuximab in HPVneg HNSCC. Thus, innovative agents to augment the efficacy of palbociclib in HPVneg HNSCC would be welcomed. A collection of 162 FDA-approved and investigational agents was screened in combinatorial matrix format, and top combinations were validated in a broader panel of HPVneg HNSCC cell lines. Transcriptional profiling was conducted to explore the molecular mechanisms of drug synergy. Finally, the most potent palbociclib-based drug combination was evaluated and compared with palbociclib plus cetuximab or cisplatin in a panel of genetically diverse HPVneg HNSCC cell lines and patient-derived xenograft models. Palbociclib displayed limited efficacy in HPVneg HNSCC as monotherapy. The high-throughput combination drug screening provided a comprehensive palbociclib-based drug-drug interaction dataset, whereas significant synergistic effects were observed when palbociclib was combined with multiple agents, including inhibitors of the PI3K, EGFR, and MEK pathways. PI3K pathway inhibitors significantly reduced cell proliferation and induced cell-cycle arrest in HPVneg HNSCC cell lines when combined with palbociclib, and alpelisib (a PI3Kα inhibitor) was demonstrated to show the most potent synergy with particularly higher efficacy in HNSCCs bearing PIK3CA alterations. Notably, when compared with cisplatin and cetuximab, alpelisib exerted stronger synergism in a broader panel of cell lines. Mechanistically, RRM2-dependent epithelial mesenchymal transition (EMT) induced by palbociclib, was attenuated by alpelisib and cetuximab rather than cisplatin. Subsequently, PDX models with distinct genetic background further validated that palbociclib plus alpelisib had significant synergistic effects in models harboring PIK3CA amplification. This study provides insights into the systematic combinatory effect associated with CDK4/6 inhibition and supports further initiation of clinical trials using the palbociclib plus alpelisib combination in HPVneg HNSCC with PIK3CA alterations. The online version contains supplementary material available at 10.1186/s12916-022-02373-6.
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影响因子：
64.5
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