Thursday, April 07, 2016 12:40:41 AM
A role for FOXO1 in BCR–ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia
link to article
You should know:
Conflict of interest
Some of the authors are employees of Roche/Genentech. We used our in-house molecules, GDC-0941 and GDC-0973, as representative PI3K and MEK kinase inhibitors, respectively. These molecules have been published and are available from commercial sources. Furthermore, our findings should be applicable to similar inhibitors from other sources. The remaining authors declare no conflict of interest.
Just side results with Ponatinib and not part of the detailed study:
Sensitivity of parental and resistant K562 and KCL-22 cell lines to multiple ABL-TKIs
The dual-resistant cell lines were generated by prolonged treatment of K562 cells with imatinib followed by dasatinib to mimic the treatment regimen that most patients receive in the clinic upon diagnosis and imatinib relapse.
We first compared the sensitivity of imatinib- and dual-resistant cells to 0–10?µm imatinib, dasatinib and ponatinib to parental controls. Figure 1a shows the response of each resistant cell line to 0.001–10?µm ABL-TKI as % growth, corrected to the day 0 growth rate and plotted relative to the DMSO control (set to 100%).
With this method, the cell growth rates after treatment are compared with those before treatment (that is, zero % growth represents cell stasis and negative % growth represents cell death).
The raw data are shown in Supplementary Figure S1. The parental K562 cell line was sensitive to imatinib (GI50: 0.3?µm), and highly sensitive to dasatinib and ponatinib treatment (GI50: <0.001?µm; Figure 1a). The imatinib-resistant cells were only resistant to imatinib, whereas the dual-resistant cells were resistant to doses of imatinib and dasatinib up to 10?µm, and even demonstrated some resistance to the ABL-TKI, ponatinib (GI50: 0.86?µm) (Figure 1a), which is efficacious against all the BCR–ABL1 kinase domain mutations including T315I.19 In contrast, the resistant KCL-22 cells were highly sensitive to ponatinib despite being resistant to both imatinib and dasatinib (Figure 1b). Altogether, these data suggest that while the KCL-22 resistant cells likely harbor a BCR–ABL1 kinase domain mutation,18 the dual-resistant K562 cells may have a BCR-ABL-independent mechanism of resistance. In support of this, the direct substrate of the BCR-ABL kinase, pCRKL, was inhibited in the dual-resistant K562 cells despite being resistant to dasatinib-mediated cell death (Supplementary Figure 2a).
So for the detailed study related to the mentioned resistance they did not use Ponatinib. Because it already did the job?
link to article
You should know:
Conflict of interest
Some of the authors are employees of Roche/Genentech. We used our in-house molecules, GDC-0941 and GDC-0973, as representative PI3K and MEK kinase inhibitors, respectively. These molecules have been published and are available from commercial sources. Furthermore, our findings should be applicable to similar inhibitors from other sources. The remaining authors declare no conflict of interest.
Just side results with Ponatinib and not part of the detailed study:
Sensitivity of parental and resistant K562 and KCL-22 cell lines to multiple ABL-TKIs
The dual-resistant cell lines were generated by prolonged treatment of K562 cells with imatinib followed by dasatinib to mimic the treatment regimen that most patients receive in the clinic upon diagnosis and imatinib relapse.
We first compared the sensitivity of imatinib- and dual-resistant cells to 0–10?µm imatinib, dasatinib and ponatinib to parental controls. Figure 1a shows the response of each resistant cell line to 0.001–10?µm ABL-TKI as % growth, corrected to the day 0 growth rate and plotted relative to the DMSO control (set to 100%).
With this method, the cell growth rates after treatment are compared with those before treatment (that is, zero % growth represents cell stasis and negative % growth represents cell death).
The raw data are shown in Supplementary Figure S1. The parental K562 cell line was sensitive to imatinib (GI50: 0.3?µm), and highly sensitive to dasatinib and ponatinib treatment (GI50: <0.001?µm; Figure 1a). The imatinib-resistant cells were only resistant to imatinib, whereas the dual-resistant cells were resistant to doses of imatinib and dasatinib up to 10?µm, and even demonstrated some resistance to the ABL-TKI, ponatinib (GI50: 0.86?µm) (Figure 1a), which is efficacious against all the BCR–ABL1 kinase domain mutations including T315I.19 In contrast, the resistant KCL-22 cells were highly sensitive to ponatinib despite being resistant to both imatinib and dasatinib (Figure 1b). Altogether, these data suggest that while the KCL-22 resistant cells likely harbor a BCR–ABL1 kinase domain mutation,18 the dual-resistant K562 cells may have a BCR-ABL-independent mechanism of resistance. In support of this, the direct substrate of the BCR-ABL kinase, pCRKL, was inhibited in the dual-resistant K562 cells despite being resistant to dasatinib-mediated cell death (Supplementary Figure 2a).
So for the detailed study related to the mentioned resistance they did not use Ponatinib. Because it already did the job?
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