The concept of targeted therapy is exemplified by the tyrosine kinase inhibitor imatinib mesylate, which is directed against the oncogenic fusion protein Bcr/abl, the underlying pathogenetic lesion of CML. The success of such agents in the treatment of CML has been taken as support for the oncogene addiction theory, which holds that such oncoproteins not only provide the cell with a survival advantage over their normal counterparts, but are, in fact, necessary for survival. In the case of CML, considerable attention has been focused on attempts to circumvent resistance to imatinib, most frequently stemming from the development of Bcr/abl mutations that prevent kinase inhibition. These efforts have led to the development of second-generation kinase inhibitors such as nilotinib, dasatinib, and bosutinib, which have enjoyed significant success in the setting of imatinib-resistant disease.
While attempts to develop more effective Bcr/abl kinase inhibitors are clearly justified, less attention has been paid to delineating the mechanisms by which interruption of Bcr/abl function triggers cell death in CML cells and, more specifically, how pharmacodynamic factors might influence this process. One important question yet to be answered is whether the degree or duration of Bcr/abl kinase inhibition is the most critical determinant of cell death. In a recent study by Shah, et al., this question was directly addressed. In brief, these investigators attempted to relate the lethality of dasatinib toward CML cells to both the degree of inhibition of Bcr/abl (and downstream targets such as CRKL), and the duration of kinase inhibition. They found that, while the duration of Bcr/abl inhibition clearly influenced dasatinib-mediated lethality, the extent of inhibition was also a key factor in triggering cell death. Intriguingly, they found that high-dose pulse therapy, which reduced kinase activity by ≥ 90 percent for a relatively brief interval, was very effective in inducing apoptosis in CML cells. The efficacy of both chronic and high-dose exposures was associated with inhibition of Bcr/abl downstream targets and induction of the BH3-only pro-apoptotic protein Bim.
In Brief
The implication of these findings is that in the case of Bcr/abl, and potentially other directed targeted therapies, both the magnitude and duration of target inhibition may play critical roles in determining treatment success or failure. They also suggest that certain molecular endpoints common to both strategies (e.g., Bim up-regulation, inhibition of Bcr/abl or CRKL) may represent useful surrogate response determinants for different treatment schedules. Finally, they raise the possibility that individual patient pharmacokinetic and pharmacogenomic characteristics could potentially guide the selection of optimal regimens (e.g., the choice between a more chronic versus a pulse high-dose schedule). In this context, it is worth noting that in a recent trial involving a FLT3 inhibitor in patients with AML, evidence suggested that lack of sustained and pronounced FLT3 inhibition by the schedule selected may have diminished its efficacy.1 Collectively, these studies indicate that a better understanding of pharmacodynamic factors responsible for cell-death induction are likely to be critical in future attempts to optimize and personalize targeted therapy in leukemia.
References
Competing Interests
Dr. Grant indicated no relevant conflicts of interest.
