Journal
TUMOR BIOLOGY
Volume 37, Issue 9, Pages 12643-12654Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-016-5179-7
Keywords
Chronicmyeloid leukemia; BCR-ABL; Tyrosine kinase inhibitor; Imatinib; Ponatinib; Forskolin
Categories
Funding
- Lizanell and Colbert Coldwell Foundation
- Edward N. and Margaret G. Marsh Foundation
- National Institute on Minority Health and Health Disparities, National Institutes of Health [2G12MD007592]
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Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.
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