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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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Related in: MedlinePlus

Tyrosine kinase inhibitors (TKIs) approved for the treatment of chronic myeloid leukemia. (a) The crystal structure of the ABL1 kinase domain is shown in complex with the indicated TKI. Highlighted residues indicate mutations that confer resistance to the indicated TKI in vitro. Orange (moderate) and red (severe) spheres indicate the level of TKI resistance. (b) The chemical structures of the TKIs. Adapted with permission from O’Hare et al. [3].
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Fig1: Tyrosine kinase inhibitors (TKIs) approved for the treatment of chronic myeloid leukemia. (a) The crystal structure of the ABL1 kinase domain is shown in complex with the indicated TKI. Highlighted residues indicate mutations that confer resistance to the indicated TKI in vitro. Orange (moderate) and red (severe) spheres indicate the level of TKI resistance. (b) The chemical structures of the TKIs. Adapted with permission from O’Hare et al. [3].

Mentions: Small molecules that inhibit oncogenic signaling pathways are redefining cancer therapy. Potential therapeutic targets have been identified in all physiological processes, reflecting the diversity of mechanisms that promote malignant transformation. In particular, tyrosine and serine/threonine kinases have attracted much attention, which is not surprising given their fundamental role in regulating eukaryotic cellular signaling [1]. Activating mutations in tyrosine and serine/threonine kinases have been identified in many types of cancer and associated with the malignant phenotype, providing a strong therapeutic rationale for the development of small molecule inhibitors that block their activity [2]. The biggest clinical successes to date are the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib and its successor compounds, dasatinib, nilotinib, bosutinib and ponatinib (Figure 1). These drugs have transformed chronic-phase chronic myeloid leukemia (CML-CP) from a lethal cancer into a chronic disorder that is compatible with a largely normal span and quality of life.Figure 1


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

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

Tyrosine kinase inhibitors (TKIs) approved for the treatment of chronic myeloid leukemia. (a) The crystal structure of the ABL1 kinase domain is shown in complex with the indicated TKI. Highlighted residues indicate mutations that confer resistance to the indicated TKI in vitro. Orange (moderate) and red (severe) spheres indicate the level of TKI resistance. (b) The chemical structures of the TKIs. Adapted with permission from O’Hare et al. [3].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Tyrosine kinase inhibitors (TKIs) approved for the treatment of chronic myeloid leukemia. (a) The crystal structure of the ABL1 kinase domain is shown in complex with the indicated TKI. Highlighted residues indicate mutations that confer resistance to the indicated TKI in vitro. Orange (moderate) and red (severe) spheres indicate the level of TKI resistance. (b) The chemical structures of the TKIs. Adapted with permission from O’Hare et al. [3].
Mentions: Small molecules that inhibit oncogenic signaling pathways are redefining cancer therapy. Potential therapeutic targets have been identified in all physiological processes, reflecting the diversity of mechanisms that promote malignant transformation. In particular, tyrosine and serine/threonine kinases have attracted much attention, which is not surprising given their fundamental role in regulating eukaryotic cellular signaling [1]. Activating mutations in tyrosine and serine/threonine kinases have been identified in many types of cancer and associated with the malignant phenotype, providing a strong therapeutic rationale for the development of small molecule inhibitors that block their activity [2]. The biggest clinical successes to date are the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib and its successor compounds, dasatinib, nilotinib, bosutinib and ponatinib (Figure 1). These drugs have transformed chronic-phase chronic myeloid leukemia (CML-CP) from a lethal cancer into a chronic disorder that is compatible with a largely normal span and quality of life.Figure 1

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