Blood, 1 August 2002, Vol. 100, No. 3, pp. 1105-1106
CORRESPONDENCE
To the editor:
Acquired resistance to imatinib mesylate: selection for
pre-existing mutant cells
Branford and colleagues have reported on the development of
resistance to imatinib mesylate in patients with chronic myeloid leukemia (CML) and with Ph+ acute lymphoblastic leukemia
(ALL) treated with this drug. Their report highlights the biologic
interest of this phenomenon, which, at the same time, is cause for
considerable concern from the clinical point of view.
These and other previous studies2-7 demonstrate that there
are various mechanisms of resistance to imatinib. In a substantial proportion of patients, the basis for resistance is a genetic change in
the BCR-ABL gene itself: particularly, point mutations within the protein tyrosine kinase (PTK) domain. This genetic mechanism
has 2 interesting implications. First, it must be highly specific for
imatinib; there is no reason to expect that there would be
cross-resistance with any other commonly used chemotherapeutic agent.
Everything leads one to believe that clinical resistance to imatinib,
just like antibiotic resistance in bacteria, arises through a process
whereby the drug itself selects for rare pre-existing mutant
cells, which gradually outgrow drug-sensitive cells. Although this will
require a very high sensitivity, it should be possible to find ways to
detect such rare mutant cells in pretreatment samples.
Second, as we all share the excitement of imatinib being the herald of
a new generation of antitumor agents,8-10 we may still have to learn some of the implications. "Conventional" cytotoxic agents target fundamental processes within the cell, such as DNA replication or the mitotic spindle. In principle, certain mutations in
any of the genes involved in one such process could confer resistance
toward a cytotoxic agent that is directed against that process. But
since the genes involved in, say, DNA replication are indispensable in
every cell, there may be enormous constraints for a mutation in any of
them to yield a cell that is drug-resistant and viable at the same
time. By contrast, since the inhibition of the normal Abl PTK by
imatinib has relatively few side effects, it must mean that its
function is dispensable in most cells, including normal granulocytes:
therefore, there may be less stringent constraints for a mutation in
the ABL gene to produce a PTK that is no longer inhibited by
imatinib in a cell that is viable. The same reasoning may be extended
to other genes that are involved in this or in any other of the
multiple signal-transduction pathways known to exist in various types
of cells and that, when mutated in tumors, are attractive
targets for new drugs11,12 Thus a relatively high
frequency of resistance mutations may be a price to pay for the target
specificity and consequent reduced toxicity of new chemotherapeutic agents.
Is this going to be a major deterrent to the use of these drugs, or
even to their development? Of course we hope not. Indeed, it is
conceivable that new analogs can be synthesized that will break through
the most common mutations conferring resistance to imatinib. But more
in general, we can perhaps apply the principles learned from infectious
diseases, where the use of a drug combination has been a time-honored
approach aiming to minimize the risk of antibiotic resistance, since
the statistical probability of a single bacterial cell having 2 rare
mutations must be very low. There is every reason to assume that the
same principles apply to mammalian somatic cells. One wonders whether,
in a not too distant future, initial therapy of CML with imatinib alone
will be frowned upon, just like single antibiotic therapy for
tuberculosis would be frowned upon today. It seems not impossible that,
just as "triple" or "quadruple" therapy is the standard of care
today for infections by M tuberculosis, a 2-drug
approach13 (perhaps cytosine-arabinoside or even the old
busulphan together with imatinib) might become the standard of care for
newly diagnosed CML.
Lucio Luzzatto and Junia V. Melo
Correspondence: Junia V. Melo, Department of Haematology,
Imperial College of Science, Technology & Medicine, Hammersmith
Hospital, Ducane Rd, London W12 ONN, United Kingdom; e-mail:
j.melo{at}ic.ac.uk
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High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
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