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.