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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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Silent mutations increase with the total number of mutations per cell clone. The graph represents the total number of silent mutations per clone (x-axis) and the percentage of clones with at least one silent mutation (blue bars). White bars represent the expected percentage of mutations. Adapted with permission from Khorashad et al. [52].
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Fig4: Silent mutations increase with the total number of mutations per cell clone. The graph represents the total number of silent mutations per clone (x-axis) and the percentage of clones with at least one silent mutation (blue bars). White bars represent the expected percentage of mutations. Adapted with permission from Khorashad et al. [52].

Mentions: Colony sequencing has been used to demonstrate linear clonal evolution in several patients who developed multidrug-resistant compound mutant clones [52]. Interestingly, the likelihood that an additional mutation is silent rather than missense increases with the total number of mutations in the BCR-ABL1 molecule (FigureĀ 4). This suggests that the fitness of the BCR-ABL1 kinase must ultimately be compromised by the acquisition of successive missense mutations, leading to evolutionary dead ends. From a therapeutic standpoint, this is good news as it suggests that mutational escape of the primary target kinase is not unlimited. As the impact on kinase fitness of two mutations in the same BCR-ABL1 allele is unpredictable, experimental validation is required [53].Figure 4


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

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

Silent mutations increase with the total number of mutations per cell clone. The graph represents the total number of silent mutations per clone (x-axis) and the percentage of clones with at least one silent mutation (blue bars). White bars represent the expected percentage of mutations. Adapted with permission from Khorashad et al. [52].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Silent mutations increase with the total number of mutations per cell clone. The graph represents the total number of silent mutations per clone (x-axis) and the percentage of clones with at least one silent mutation (blue bars). White bars represent the expected percentage of mutations. Adapted with permission from Khorashad et al. [52].
Mentions: Colony sequencing has been used to demonstrate linear clonal evolution in several patients who developed multidrug-resistant compound mutant clones [52]. Interestingly, the likelihood that an additional mutation is silent rather than missense increases with the total number of mutations in the BCR-ABL1 molecule (FigureĀ 4). This suggests that the fitness of the BCR-ABL1 kinase must ultimately be compromised by the acquisition of successive missense mutations, leading to evolutionary dead ends. From a therapeutic standpoint, this is good news as it suggests that mutational escape of the primary target kinase is not unlimited. As the impact on kinase fitness of two mutations in the same BCR-ABL1 allele is unpredictable, experimental validation is required [53].Figure 4

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