HDAC Inhibitors to the Rescue

Histone deacetylase inhibitors (HDACIs) are commonly grouped, along with the prototypical Bcr/abl kinase inhibitor imatinib mesylate, as representative targeted agents. However, HDACIs are truly chameleon-like molecules, which, in addition to modifying chromatin structure, and, by extension, gene expression, trigger acetylation of diverse proteins, including chaperone and DNA repair proteins, as well transcription factors, among numerous others. Given their pleiotropic actions, HDACIs have proven to be very effective, at least in the preclinical setting, in potentiating the activity of not only standard cytotoxic agents, but also other targeted signal transduction inhibitors. For example, multiple groups have reported that HDACIs, and particularly pan-HDACIs, potentiate the anti-leukemic effects of imatinib and other Bcr/abl kinase inhibitors in CML cells through a variety of mechanisms, including enhancing inactivation of Bcr/abl.^1,2

Aside from the issue of the emergence or pre-existence of Bcr/abl kinase inhibitor resistance, a major theoretical barrier to curative approaches to CML is the possibility that such agents may be incapable of eradicating CML stem or leukemia-initiating cells. Indeed, preclinical evidence suggests that Bcr/ abl kinase inhibitors are relatively ineffective in killing cytokinetically quiescent CML stem cells.³  Assuming failure to eradicate such stems cells represents a legitimate clinical issue, the question then remains whether addition of an HDACI would help to overcome this problem.

Zhang et al. from the Bhatia laboratory at City of Hope National Medical Center in California addressed this question directly for the first time. They reported that co-treatment with imatinib and the pan-HDACI LBH-589 effectively induced apoptosis in non-proliferating, otherwise imatinib-resistant CML progenitor cells and significantly reduced their capacity to repopulate the marrows of immunodeficient mice. Importantly, co-administration of HDACIs with imatinib proved very potent in reducing the number of putative CML stem cells in a transgenic mouse model of CML. The authors conclude that if the results of this study can be extrapolated to humans with CML such that residual LSCs can be reduced, HDACIs might enhance the ability of patients to maintain long-term remissions following discontinuation of Bcr/abl kinase inhibitor treatment.