Multiple Resistance Mechanisms Identified through Studies of Cell Lines Derived from Chronic Myelogenous Leukemia Patients Progressing on STI-571 Therapy
Presenter: Nicholas J. Donato
Presenter's Affiliation: MD Anderson Cancer Center
Type of Session: Scientific
STI-571 is known to be an effective inhibitor of the BCR-ABL fusion protein and therefore has become a common treatment for BCR-ABL positive leukemias.
Disease progression while on STI-571 occurs frequently in accelerated and blast crisis patients.
In this study, several cell lines from leukemia patients progressing on STI-571 were established and analyzed for potential mechanisms of resistance.
Putative mechanisms of resistance include pharmacologic and metabolic changes as well as BCR-ABL gene amplification and mutation.
Materials and Methods
6 cell lines from accelerated phase or blast crisis patients with STI-571 positive leukemias were succesfully created. These cells were assayed for in-vitro STI-571 resistance, BCR-ABL transcription and translation as well as upregulation of other tyrosine kinases.
The K-562 cell line was used as a control.
All cell lines retained the (9:22)translocation. Multiple and variable other cytogenetic abnormalities were also seen.
Great heterogeneity in transcription of BCR-ABL was found by RT-PCR among the various cell lines.
Several cell lines showed in-vitro sensitivity to STI-571 despite their origin in patients progressing on this therapy.
Great variation in BCR-ABL protein expression was seen. Resistance was associated with decreased expression of the protein.
An increase in Lyn and Hck kinase expression was documented in the most cell lines most resistant to STI-571.
Cell lines have been established allowing for in-vitro testing for mechanisms of STI-571 resistance.
Several of these cell lines retain in-vitro sensitivity to STI-571 indicating the possible presence of pharmacologic resistance mechanisms.
Resistance correlates with decreased expression of BCR-ABL and corresponding upregulation of other protein kinases including Lyn and Hck kinases.
These cell lines may be useful in investigating other novel mechanisms of treatment resistance.
This study provides further evidence that there are multiple mechanisms of STI-571 resistance in leukemia, in particular, activation of BCR-ABL independent tyrosine kinase cascades which bypass BCR-ABL completely. Study of these cell lines may provide further targets of interest allowing us to counter these mechanisms of resistance.
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