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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

Multiple mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia. The schematic portrays multiple mechanisms of TKI resistance, including BCR-ABL1 kinase-dependent mechanisms (top) and BCR-ABL1 kinase-independent mechanisms (bottom). Certain tyrosine kinase mutations impart increased or decreased fitness on the BCR-ABL1 kinase. Other mutations such as T315I impart high-level resistance to first- and second-generation TKIs. Cells that carry resistance mutations may impart resistance on neighboring bystander cells by secretion of paracrine factors (such as the cytokine IL-3), so that even cells with native BCR-ABL1 become TKI resistant. Last, CML cells may acquire resistance through intrinsic activation of alternative signaling pathways or through interaction with the bone marrow microenvironment. Red and green dots denote paracrine factors produced by leukemic cells or the bone marrow microenvironment.
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Fig2: Multiple mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia. The schematic portrays multiple mechanisms of TKI resistance, including BCR-ABL1 kinase-dependent mechanisms (top) and BCR-ABL1 kinase-independent mechanisms (bottom). Certain tyrosine kinase mutations impart increased or decreased fitness on the BCR-ABL1 kinase. Other mutations such as T315I impart high-level resistance to first- and second-generation TKIs. Cells that carry resistance mutations may impart resistance on neighboring bystander cells by secretion of paracrine factors (such as the cytokine IL-3), so that even cells with native BCR-ABL1 become TKI resistant. Last, CML cells may acquire resistance through intrinsic activation of alternative signaling pathways or through interaction with the bone marrow microenvironment. Red and green dots denote paracrine factors produced by leukemic cells or the bone marrow microenvironment.

Mentions: Second, BCR-ABL1 kinase-independent resistance is thought to occur when alternative signaling pathways are activated that maintain cell proliferation and viability despite continued suppression of BCR-ABL1 kinase activity (Figure 2) [3]. Evidence suggests that both extrinsic and intrinsic mechanisms are involved in BCR-ABL1 kinase-independent resistance and may activate the same downstream signaling molecules. Multiple extrinsic and intrinsic signals and pathways have been implicated, including JAK/STAT [30–32], phosphatidyl inositol 3′ kinase (PI3K) [33], Wnt/β-catenin [34–36], SHP-1 [37], SRC family kinases such as Lyn [38], and polymorphisms of the pro-apoptosis protein BIM [39]. The mechanistic heterogeneity of BCR-ABL1 kinase-independent TKI resistance poses a diagnostic and therapeutic challenge. Hence, individualized TKI therapy as it exists today centers on BCR-ABL1 kinase domain mutations, and BCR-ABL1 kinase-dependent resistance will be the focus of this review.Figure 2


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

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

Multiple mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia. The schematic portrays multiple mechanisms of TKI resistance, including BCR-ABL1 kinase-dependent mechanisms (top) and BCR-ABL1 kinase-independent mechanisms (bottom). Certain tyrosine kinase mutations impart increased or decreased fitness on the BCR-ABL1 kinase. Other mutations such as T315I impart high-level resistance to first- and second-generation TKIs. Cells that carry resistance mutations may impart resistance on neighboring bystander cells by secretion of paracrine factors (such as the cytokine IL-3), so that even cells with native BCR-ABL1 become TKI resistant. Last, CML cells may acquire resistance through intrinsic activation of alternative signaling pathways or through interaction with the bone marrow microenvironment. Red and green dots denote paracrine factors produced by leukemic cells or the bone marrow microenvironment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Multiple mechanisms of tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia. The schematic portrays multiple mechanisms of TKI resistance, including BCR-ABL1 kinase-dependent mechanisms (top) and BCR-ABL1 kinase-independent mechanisms (bottom). Certain tyrosine kinase mutations impart increased or decreased fitness on the BCR-ABL1 kinase. Other mutations such as T315I impart high-level resistance to first- and second-generation TKIs. Cells that carry resistance mutations may impart resistance on neighboring bystander cells by secretion of paracrine factors (such as the cytokine IL-3), so that even cells with native BCR-ABL1 become TKI resistant. Last, CML cells may acquire resistance through intrinsic activation of alternative signaling pathways or through interaction with the bone marrow microenvironment. Red and green dots denote paracrine factors produced by leukemic cells or the bone marrow microenvironment.
Mentions: Second, BCR-ABL1 kinase-independent resistance is thought to occur when alternative signaling pathways are activated that maintain cell proliferation and viability despite continued suppression of BCR-ABL1 kinase activity (Figure 2) [3]. Evidence suggests that both extrinsic and intrinsic mechanisms are involved in BCR-ABL1 kinase-independent resistance and may activate the same downstream signaling molecules. Multiple extrinsic and intrinsic signals and pathways have been implicated, including JAK/STAT [30–32], phosphatidyl inositol 3′ kinase (PI3K) [33], Wnt/β-catenin [34–36], SHP-1 [37], SRC family kinases such as Lyn [38], and polymorphisms of the pro-apoptosis protein BIM [39]. The mechanistic heterogeneity of BCR-ABL1 kinase-independent TKI resistance poses a diagnostic and therapeutic challenge. Hence, individualized TKI therapy as it exists today centers on BCR-ABL1 kinase domain mutations, and BCR-ABL1 kinase-dependent resistance will be the focus of this review.Figure 2

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