Reference Detail

Ref Type Journal Article
PMID (28428442)
Authors Kuo HP, Ezell SA, Schweighofer KJ, Cheung LWK, Hsieh S, Apatira M, Sirisawad M, Eckert K, Hsu SJ, Chen CT, Beaupre DM, Versele M, Chang BY
Title Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma.
Journal Molecular cancer therapeutics
Vol 16
Issue 7
Date 2017 Jul
URL
Abstract Text Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton tyrosine kinase (BTK)-mediated B-cell receptor 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 follicular 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. Mol Cancer Ther; 16(7); 1246-56. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown follicular lymphoma not applicable Ibrutinib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Imbruvica (ibrutinib) and Venclexta (venetoclax) resulted in a synergistic effect, demonstrating growth suppression in follicular lymphoma cell lines in culture (PMID: 28428442). 28428442
Unknown unknown diffuse large B-cell lymphoma not applicable Ibrutinib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, the combination of Imbruvica (ibrutinib) and Venclexta (venetoclax) resulted in a synergistic effect, demonstrating growth suppression in germinal center B-cell diffuse large B-cell lymphoma (DLBCL) cell lines in culture, increased apoptotic activity and inhibition of colony formation in activated B-cell (ABC) DLBCL cell lines, and complete tumor growth inhibition in ABC-DLBCL cell line xenograft models (PMID: 28428442). 28428442