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对一种对Chk1抑制剂PF-00477736耐药的套细胞淋巴瘤细胞系的鉴定

Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736.

作者信息

Restelli Valentina, Chilà Rosaria, Lupi Monica, Rinaldi Andrea, Kwee Ivo, Bertoni Francesco, Damia Giovanna, Carrassa Laura

机构信息

Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.

出版信息

Oncotarget. 2015 Nov 10;6(35):37229-40. doi: 10.18632/oncotarget.5954.

DOI:10.18632/oncotarget.5954
PMID:26439697
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4741926/
Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the chromosomal translocation t(11;14) that leads to constitutive expression of cyclin D1, a master regulator of the G1-S phase. Chk1 inhibitors have been recently shown to be strongly effective as single agents in MCL. To investigate molecular mechanisms at the basis of Chk1 inhibitor activity, a MCL cell line resistant to the Chk1 inhibitor PF-00477736 (JEKO-1 R) was obtained and characterized. The JEKO-1 R cell line was cross resistant to another Chk1 inhibitor (AZD-7762) and to the Wee1 inhibitor MK-1775. It displayed a shorter doubling time than parental cell line, likely due to a faster S phase. Cyclin D1 expression levels were decreased in resistant cell line and its re-overexpression partially re-established PF-00477736 sensitivity. Gene expression profiling showed an enrichment in gene sets involved in pro-survival pathways in JEKO-1 R. Dasatinib treatment partly restored PF-00477736 sensitivity in resistant cells suggesting that the pharmacological interference of pro-survival pathways can overcome the resistance to Chk1 inhibitors. These data further corroborate the involvement of the t(11;14) in cellular sensitivity to Chk1 inhibitors, fostering the clinical testing of Chk1 inhibitors as single agents in MCL.

摘要

套细胞淋巴瘤（MCL）是一种侵袭性B细胞淋巴瘤，其特征在于染色体易位t(11;14)，该易位导致细胞周期蛋白D1（G1-S期的主要调节因子）的组成性表达。最近研究表明，Chk1抑制剂作为单一药物在MCL中具有强效作用。为了研究Chk1抑制剂活性的分子机制，我们获得并鉴定了一种对Chk1抑制剂PF-00477736耐药的MCL细胞系（JEKO-1 R）。JEKO-1 R细胞系对另一种Chk1抑制剂（AZD-7762）和Wee1抑制剂MK-1775具有交叉耐药性。它的倍增时间比亲代细胞系短，这可能是由于S期更快。在耐药细胞系中细胞周期蛋白D1的表达水平降低，其重新过表达部分恢复了对PF-00477736的敏感性。基因表达谱显示，JEKO-1 R中参与促生存途径的基因集富集。达沙替尼治疗部分恢复了耐药细胞对PF-00477736的敏感性，这表明对促生存途径的药理学干扰可以克服对Chk1抑制剂的耐药性。这些数据进一步证实了t(11;14)与细胞对Chk1抑制剂的敏感性有关，推动了Chk1抑制剂作为单一药物在MCL中的临床试验。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/0050468c9c2f/oncotarget-06-37229-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/88db74e57744/oncotarget-06-37229-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/12582c35a9ca/oncotarget-06-37229-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/66ac6bd185fd/oncotarget-06-37229-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/16e9b86c5e00/oncotarget-06-37229-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/4f02ce96a9ff/oncotarget-06-37229-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/0050468c9c2f/oncotarget-06-37229-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/88db74e57744/oncotarget-06-37229-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/12582c35a9ca/oncotarget-06-37229-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/66ac6bd185fd/oncotarget-06-37229-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/16e9b86c5e00/oncotarget-06-37229-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/4f02ce96a9ff/oncotarget-06-37229-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e4d/4741926/0050468c9c2f/oncotarget-06-37229-g006.jpg

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