Potential mechanisms of resistance to venetoclax and strategies to circumvent it

BMC Cancer

Research Article

Lisa Roberts Rapp¹  Stephen K. Tahir¹  Chang H. Park¹  Paul Hessler¹  Kenneth B. Idler¹  Lloyd T. Lam¹  Morey L. Smith¹  Joel D. Leverson¹ 

[1] AbbVie Oncology, North Waukegan Road North, 60064-6098, Chicago, IL, USA;

关键词: BCL-2;    BCL-X;    MCL-1;    Apoptosis;   

DOI  :  10.1186/s12885-017-3383-5

 received in 2016-08-26, accepted in 2017-05-24,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundVenetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges.MethodsIn order to gain a more comprehensive insight into the nature of venetoclax resistance mechanisms, we evaluated the changes in the BCL-2 family members at the genetic and expression levels in seven different venetoclax-resistant derived leukemia and lymphoma cell lines.ResultsGene and protein expression analyses identified a number of different alterations in the expression of pro- and anti-apoptotic BCL-2 family members. In the resistant derived cells, an increase in either or both the anti-apoptotic proteins BCL-XL or MCL-1, which are not targeted by venetoclax was observed, and either concomitant or exclusive with a decrease in one or more pro-apoptotic proteins. In addition, mutational analysis also revealed a mutation in the BH3 binding groove (F104L) that could potentially interfere with venetoclax-binding. Not all changes may be causally related to venetoclax resistance and may only be an epiphenomenon. For resistant cell lines showing elevations in BCL-XL or MCL-1, strong synergistic cell killing was observed when venetoclax was combined with either BCL-XL- or MCL-1-selective inhibitors, respectively. This highlights the importance of BCL-XL- and MCL-1 as causally contributing to venetoclax resistance.ConclusionsOverall our study identified numerous changes in multiple resistant lines; the changes were neither mutually exclusive nor universal across the cell lines tested, thus exemplifying the complexity and heterogeneity of potential resistance mechanisms. Identifying and evaluating their contribution has important implications for both patient selection and the rational development of strategies to overcome resistance.

【 授权许可】

CC BY   
© The Author(s). 2017