Abstract
Tyrosine Kinase Inhibitors and Phosphatases: Overcoming the BCR-ABL T315I Mutation in CML with a Synergistic Combination of Ponatinib and Forskolin
Highlights
Tyrosine Kinase Inhibitors and Phosphatases: Overcoming the BCR-ABL T315I Mutation in chronic myeloid leukemia (CML) with a Synergistic Combination of Ponatinib and Forskolin
Various mechanisms lead to tyrosine kinase inhibitor (TKI) resistance, one of the most clinically significant is the result of a T315I mutation within the BCR-ABL kinase domain that directly impacts the binding of all first and second generation TKIs, by removal of a key hydrogen bond necessary for TKI binding [6]
The T315I mutation has been associated with a poor clinical outcome, and poses a major hurdle for treating CML due to the lack of TKIs capable of binding BCR-ABLT315I [7]
Summary
Tyrosine Kinase Inhibitors and Phosphatases: Overcoming the BCR-ABL T315I Mutation in CML with a Synergistic Combination of Ponatinib and Forskolin. The initial treatment of CML revolves around targeting the kinase activity of BCR-ABL, by utilizing a first generation tyrosine kinase inhibitor (TKI) imatinib [2]. Second generation TKIs, such as dasatinib, were developed to target BCR-ABL with more potent capabilities to overcome disease resistance to first line TKI treatment [3].
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