Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine

Abstract

BH3 mimetics such as ABT-737 and navitoclax bind to the BCL-2 family of proteins and induce apoptosis through the intrinsic apoptosis pathway. There is considerable variability in the sensitivity of different cells to these drugs. Understanding the molecular basis of this variability will help to determine which patients will benefit from these drugs. Furthermore, this understanding aids in the design of rational strategies to increase the sensitivity of cells which are otherwise resistant to BH3 mimetics. We discuss how the expression of BCL-2 family proteins regulates the sensitivity to ABT-737. One of these, MCL-1, has been widely described as contributing to resistance to ABT-737 which might suggest a poor response in patients with cancers that express levels of MCL-1. In some cases, resistance to ABT-737 conferred by MCL-1 is overcome by the expression of pro-apoptotic proteins that bind to apoptosis inhibitors such as MCL-1. However, the distribution of the pro-apoptotic proteins amongst the various apoptosis inhibitors also influences sensitivity to ABT-737. Furthermore, the expression of both pro- and anti-apoptotic proteins can change dynamically in response to exposure to ABT-737. Thus, there is significant complexity associated with predicting response to ABT-737. This provides a paradigm for the multiplicity of intricate factors that determine drug sensitivity which must be considered for the full implementation of personalized medicine.

Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP

“…Several chemotherapeutic agents have shown synergy with ABT-263 based on two main mechanisms, either decreased expression of Mcl-1 or increased expression of BH3-only proteins (31). BMN 673 treatment neither decreased the expression of Mcl-1 nor increased the expression of BH3-only proteins.…”

“…It has been reported that ABT-263 posttranscriptionally upregulates Mcl-1 expression through ERK-mediated phosphorylation of Mcl-1 on Thr-163 (33,34). Mcl-1 confers resistance to ABT-263 because it remains a potent anti-apoptotic protein (31). However, expression of Mcl-1 is not always sufficient to cause resistance to ABT-263 given that occupancy of Mcl-1 by pro-apoptotic proteins can effectively inactivate Mcl-1 (15,35,36).…”

Yeast techniques for modeling drugs targeting Bcl-2 and caspase family members

“…14, 16 Overexpression of ABT-263-resistant Bcl-2 relatives such as A1 and Mcl-1 rendered some tumors resistant to ABT-263. 17 Hence, the ability of ABT-263 to promote regression of some tumors demonstrated the utility of targeting the Bcl-2 family for cancer treatment, but the drug's limitations highlight the need to develop other BH3-mimetics with distinct specificities.…”

The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cellsin vitro, as a single agent and in combination with other drugs

“…Bortezomib has been investigated in vitro in CLL and other cancers in combination with several BCL2 inhibitors, including obatoclax (Perez-Galan et al, 2008), HA14-1 (Pei et al, 2003) and oblimersen sodium (BCL2 anti-sense oligonucleotide) (O'Connor et al, 2006) with favourable results. However, these BCL2 inhibitors are primarily selective for BCL2 only, or only weakly bind other anti-apoptotic BCL2 members, limiting their use in lymphoid malignancies where MCL1 and BCL2L1 (BCL-XL) also play a critical role in tumour cell survival (Beroukhim et al, 2010;Davids & Letai, 2012;Stamelos et al, 2012). Of particular interest is AT-101, which is the R-(-)-enantiomer of gossypol and is a small molecule pan-BCL2 inhibitor that binds to the BH3 domains of anti-apoptotic BCL2 proteins and disrupts their functional activity.…”