期刊
ONCOGENE
卷 35, 期 48, 页码 6223-6234出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.155
关键词
-
资金
- UW-Madison Start-up funds
- KL2 Scholar Award [UL1TR0000427, KL2TR000428]
- NIH [R01 CA187299]
- MACC fund
- National Institutes of Health/National Cancer Institute [K08 CA174750]
- USDA National Institute of Food and Agriculture [Hatch 1002874]
- UW Forward Lymphoma Fund
- University of Wisconsin Carbone Cancer Center (UWCCC)
- NIH/NCI UW Comprehensive Cancer Center Support [P30 CA014520]
Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-kappa B activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据