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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1070-1079
Selection and characterization of BCR-ABL positive cell
lines with differential sensitivity to the tyrosine kinase
inhibitor STI571: diverse mechanisms of resistance
François Xavier Mahon,
Michael W. N. Deininger,
Beate Schultheis,
Jérome Chabrol,
Josy Reiffers,
John M. Goldman, and
Junia V. Melo
From the Department of Haematology, Imperial College School
of Science, Technology and Medicine, Hammersmith Hospital, London, UK;
and the Laboratoire Greffe de Moelle, Université Victor Segalen,
Bordeaux, France.
Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an
attractive therapeutic strategy in chronic myelogenous leukemia (CML).
A few CML cell lines and primary progenitors are, however, resistant to
this compound. We investigated the mechanism of this resistance in
clones of the murine BaF/3 cells transfected with BCR-ABL and
in 4 human cell lines from which sensitive (s) and resistant (r) clones
were generated by various methods. Although the resistant cells were
able to survive in the presence of STI571, their proliferation was
approximately 30% lower than that of their sensitive counterparts in
the absence of the compound. The concentration of STI571 needed for a
50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 µmol/L) than in the sensitive
(0.2-0.25 µmol/L) clones. The mechanism of resistance to STI571
varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r,
and AR230-r, there was up-regulation of the Bcr-Abl protein associated
with amplification of the BCR-ABL gene. In K562-r, there was no
Bcr-Abl overexpression, but the IC50 for the inhibition of
Bcr-Abl autophosphorylation was increased in the resistant clones.
Sequencing of the Abl kinase domain revealed no mutations. The
multidrug resistance P-glycoprotein (Pgp) was overexpressed in
LAMA84-r, indicating that at least 2 mechanisms of resistance operate
in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a
higher threshold for tyrosine kinase inhibition by STI571. We conclude
that BCR-ABL-positive cells can evade the inhibitory effect of
STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced
intake mediated by Pgp, and, possibly, acquisition of compensatory
mutations in genes other than BCR-ABL.
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Related Letter in Blood Online:
-
Another possible mechanism of resistance to STI571
- Zachary A. Knight;, Carlo Gambacorti-Passerini, Philipp le Coutre, Elena Tassi, and Holger Ruchatz
Blood 2000 96: 4003-4005.
[Full Text]
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