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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3498-3505
Mechanism of resistance to the ABL tyrosine kinase inhibitor
STI571 in BCR/ABL-transformed hematopoietic cell lines
Ellen Weisberg and
James D. Griffin
From the Department of Adult Oncology, Dana Farber Cancer Institute,
Department of Medicine, Brigham and Women's Hospital, and Department
of Medicine, Harvard Medical School, Boston, MA.
The tyrosine kinase activity of the Bcr/Abl oncogene is required for
transformation of hematopoietic cells. The tyrosine kinase inhibitor
STI571 (formerly called CGP57148B, Novartis Pharmaceuticals) inhibits
BCR/ABL, TEL/ABL, and v-ABL kinase activity and inhibits growth and
viability of cells transformed by any of these ABL oncogenes. Here we
report the generation of 2 BCR/ABL-positive cell lines that have
developed partial resistance to STI571. BCR/ABL-transformed Ba/F3
hematopoietic cells and Philadelphia-positive human K562 cells were cultured in gradually increasing concentrations of STI571
over a period of several months to generate resistant lines. Resistant
Ba/F3.p210 cells were found to have an increase in Bcr/Abl messenger
RNA, amplification of the Bcr/Abl transgene, and a greater than tenfold
increase in the level of BCR/ABL protein. In contrast to Ba/F3.p210
cells, drug-resistant K562 cells did not undergo detectable
amplification of the BCR/ABL gene, although they displayed a 2-fold to
3-fold increase in p210BCR/ABL protein. The addition of STI571 to both
resistant Ba/F3.p210 and K562 cells resulted in a rapid reduction of
tyrosine phosphorylation of cellular proteins, similar to that observed
for nonresistant cells. However, the inhibition of kinase activity was
transient and partial and was not accompanied by apoptosis. The results
suggest that resistance to STI571 may be multifactorial. Increased
expression of the target protein BCR/ABL was observed in both lines,
and resulted from oncogene amplification in one line. However, altered
drug metabolism, transport, or other related mechanisms may also
contribute to drug resistance.
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Related Letter in Blood Online:
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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.
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