Abstract
Purpose: B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting.Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition.Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. Clin Cancer Res; 24(16); 3967-80. ©2018 AACR.
Highlights
Impaired apoptosis has been shown to play an important role in the tumorigenesis of a large number of cancers [1, 2]
We demonstrate that diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines, primary patient samples, and patient-derived xenograft (PDX) mouse models expressing high B-cell lymphoma 2 (BCL-2) levels are extremely sensitive to venetoclax treatment
8/15 (53%) GCBDLBCL, 3/8 (38%) non-GCB-DLBCL, and 8/10 (80%) MCL cell lines were sensitive to venetoclax (IC50 100 nmol/L), whereas the other cell lines were more resistant to venetoclax (IC50 > 100 nmol/L; Fig. 1A)
Summary
Impaired apoptosis has been shown to play an important role in the tumorigenesis of a large number of cancers [1, 2]. Apoptosis is closely regulated by the B-cell lymphoma 2 (BCL-2) family of proteins, and BCL-2, one of the first identified members of this. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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