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Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia.

Eiring AM, Deininger MW - Genome Biol. (2014)

Bottom Line: The success of tyrosine kinase inhibitors in treating chronic myeloid leukemia highlights the potential of targeting oncogenic kinases with small molecules.By using drug activity profiles and individual patient genotypes, one can guide personalized therapy selection for patients with resistance.

View Article: PubMed Central - PubMed

ABSTRACT
The success of tyrosine kinase inhibitors in treating chronic myeloid leukemia highlights the potential of targeting oncogenic kinases with small molecules. By using drug activity profiles and individual patient genotypes, one can guide personalized therapy selection for patients with resistance.

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Activities of imatinib, bosutinib, dasatinib, nilotinib, and ponatinib against mutated forms of BCR-ABL1. Half maximal inhibitory concentration (IC50) values for cell proliferation of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates the IC50 sensitivity for each TKI relative to its activity against cells expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as the drug concentrations achieved in the plasma of patients. Adapted with permission from Redaelli et al. [57].
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Fig3: Activities of imatinib, bosutinib, dasatinib, nilotinib, and ponatinib against mutated forms of BCR-ABL1. Half maximal inhibitory concentration (IC50) values for cell proliferation of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates the IC50 sensitivity for each TKI relative to its activity against cells expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as the drug concentrations achieved in the plasma of patients. Adapted with permission from Redaelli et al. [57].

Mentions: Despite many improvements, all second-generation TKIs share a common vulnerability with imatinib, namely the T315I mutation of the ‘gatekeeper’ residue in ABL1 [3]. Substitution of threonine 315 with isoleucine prevents the formation of a key hydrogen bond (or van der Waals interaction in the case of bosutinib) between the kinase and the TKI drug, resulting in high-level resistance to multiple TKIs (Figure 2). Additionally, access to a hydrophobic pocket that is engaged by all first- and second-generation TKIs is blocked by this substitution. Ponatinib, the only third-generation TKI approved to date, is a type II inhibitor that was designed to avoid T315 by inclusion of a rigid triple carbon bond (Figure 1) [24]. Higher concentrations of ponatinib are required for inhibition of certain BCR-ABL1 mutants (for example, E255V), but these are still within the range of plasma concentrations achievable in patients, and clinical responses have been observed in patients who harbor these genotypes [24]. In vitro assays based on culturing cells that express randomly mutagenized BCR-ABL1 in the presence of TKIs are remarkably accurate in predicting clinically relevant BCR-ABL1 resistance mutations and contact points between TKIs and the kinase domains. Mutagenesis is achieved either by initial expression of a BCR-ABL1 plasmid in a mutagenic bacterial strain or by exposing the BCR-ABL1-expressing cells to N-nitroso-N-methylurea (ENU). Despite the fact that in vivo activity is dependent on multiple additional factors, including bioavailability, achievable plasma concentrations, transmembrane transport and protein binding, the in vitro drug sensitivity of cell lines (typically the pro-B cell line BaF/3, engineered to express BCR-ABL1 mutants in comparison to the native BCR-ABL1 kinase) is generally correlated with clinical activity (Figure 3). This allows rational TKI selection on the basis of the patient’s BCR-ABL1 genotype, and provides an example of how molecular knowledge can aid the personalization of cancer therapy.Figure 3


Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia.

Eiring AM, Deininger MW - Genome Biol. (2014)

Activities of imatinib, bosutinib, dasatinib, nilotinib, and ponatinib against mutated forms of BCR-ABL1. Half maximal inhibitory concentration (IC50) values for cell proliferation of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates the IC50 sensitivity for each TKI relative to its activity against cells expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as the drug concentrations achieved in the plasma of patients. Adapted with permission from Redaelli et al. [57].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318205&req=5

Fig3: Activities of imatinib, bosutinib, dasatinib, nilotinib, and ponatinib against mutated forms of BCR-ABL1. Half maximal inhibitory concentration (IC50) values for cell proliferation of the indicated TKIs are shown against BCR-ABL1 single mutants. The color gradient demonstrates the IC50 sensitivity for each TKI relative to its activity against cells expressing native BCR-ABL1. Note that clinical activity is also dependent on additional factors, such as the drug concentrations achieved in the plasma of patients. Adapted with permission from Redaelli et al. [57].
Mentions: Despite many improvements, all second-generation TKIs share a common vulnerability with imatinib, namely the T315I mutation of the ‘gatekeeper’ residue in ABL1 [3]. Substitution of threonine 315 with isoleucine prevents the formation of a key hydrogen bond (or van der Waals interaction in the case of bosutinib) between the kinase and the TKI drug, resulting in high-level resistance to multiple TKIs (Figure 2). Additionally, access to a hydrophobic pocket that is engaged by all first- and second-generation TKIs is blocked by this substitution. Ponatinib, the only third-generation TKI approved to date, is a type II inhibitor that was designed to avoid T315 by inclusion of a rigid triple carbon bond (Figure 1) [24]. Higher concentrations of ponatinib are required for inhibition of certain BCR-ABL1 mutants (for example, E255V), but these are still within the range of plasma concentrations achievable in patients, and clinical responses have been observed in patients who harbor these genotypes [24]. In vitro assays based on culturing cells that express randomly mutagenized BCR-ABL1 in the presence of TKIs are remarkably accurate in predicting clinically relevant BCR-ABL1 resistance mutations and contact points between TKIs and the kinase domains. Mutagenesis is achieved either by initial expression of a BCR-ABL1 plasmid in a mutagenic bacterial strain or by exposing the BCR-ABL1-expressing cells to N-nitroso-N-methylurea (ENU). Despite the fact that in vivo activity is dependent on multiple additional factors, including bioavailability, achievable plasma concentrations, transmembrane transport and protein binding, the in vitro drug sensitivity of cell lines (typically the pro-B cell line BaF/3, engineered to express BCR-ABL1 mutants in comparison to the native BCR-ABL1 kinase) is generally correlated with clinical activity (Figure 3). This allows rational TKI selection on the basis of the patient’s BCR-ABL1 genotype, and provides an example of how molecular knowledge can aid the personalization of cancer therapy.Figure 3

Bottom Line: The success of tyrosine kinase inhibitors in treating chronic myeloid leukemia highlights the potential of targeting oncogenic kinases with small molecules.By using drug activity profiles and individual patient genotypes, one can guide personalized therapy selection for patients with resistance.

View Article: PubMed Central - PubMed

ABSTRACT
The success of tyrosine kinase inhibitors in treating chronic myeloid leukemia highlights the potential of targeting oncogenic kinases with small molecules. By using drug activity profiles and individual patient genotypes, one can guide personalized therapy selection for patients with resistance.

Show MeSH
Related in: MedlinePlus