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| Status |
Public on Apr 30, 2017 |
| Title |
Gene expression data of parental and ibrutinib-resistant TMD8 cells. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.
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| Overall design |
Gene expression in parental or ibrutinib-resistant TMD8 cells was detected by HTA2.0 arrays and the level of BCL2 expression was compared between these two groups.
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| Contributor(s) |
Kuo H, Ezell SA, Schweighofer KJ, Cheung LW, Hsieh S, Apatira M, Sirisawad M, Eckert K, Hsu J, Chen C, Beaupre D, Versele M, Chang BY |
| Citation(s) |
28428442 |
| Submission date |
Jan 24, 2017 |
| Last update date |
Oct 29, 2018 |
| Contact name |
Hsu-Ping Kuo |
| E-mail(s) |
hkuo@pcyc.com
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| Phone |
4082153739
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| Organization name |
Pharmacyclics
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| Street address |
995 E Arques Ave
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| City |
Sunnyvale |
| State/province |
CA |
| ZIP/Postal code |
94087 |
| Country |
USA |
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| Platforms (1) |
| GPL17586 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE93986 |
Expression data from DLBCL tumor biopsies and TMD8 cell line |
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| Relations |
| BioProject |
PRJNA363009 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE93985_RAW.tar |
103.5 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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