FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.

Therapeutic Approaches

Abstract

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-κB 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.Oncogene advance online publication, 9 May 2016; doi:10.1038/onc.2016.155.

Authors

Li, Y; Bouchlaka, M N; Wolff, J; Grindle, K M; Lu, L; Qian, S; Zhong, X; Pflum, N; Jobin, P; Kahl, B S; Eickhoff, J C; Wuerzberger-Davis, S M; Miyamoto, S; Thomas, Craig; Yang, D T; Capitini, C M; Rui, L;

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