By Steven Grant, MD
2009-05-01
Dr. Grant indicated no relevant conflicts of interest.
Shah NP, Kasap C, Weier C, et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell. 2008;14:485-93.
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.
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.
- Pratz KW, Cortes J, Roboz GJ, et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood. 2008. [Epub ahead of print]
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