Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance

Ping Hui Tseng, Ho Pi Lin, Jiuxiang Zhu, Kuen Feng Chen, Erinn M. Hade, Donn C. Young, John C. Byrd, Michael Grever, Kara Johnson, Brian Druker, Ching Shih Chen

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210 T3151. The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210E255K and Ba/F3p210T3151 were 14 ± 4 and 30 ± 2 μM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 μM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.

Original languageEnglish (US)
Pages (from-to)4021-4027
Number of pages7
JournalBlood
Volume105
Issue number10
DOIs
StatePublished - May 15 2005
Externally publishedYes

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1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Phosphotransferases
Inhibitory Concentration 50
Celecoxib
Cells
abl Genes
Apoptosis
Leukemia, Myeloid, Chronic Phase
Proto-Oncogene Proteins c-akt
OSU 03012
Imatinib Mesylate
Point Mutation
Protein-Tyrosine Kinases
Tyrosine
Tumors
Cell Survival
Cell Line
Mutation
Neoplasms

ASJC Scopus subject areas

  • Hematology

Cite this

Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance. / Tseng, Ping Hui; Lin, Ho Pi; Zhu, Jiuxiang; Chen, Kuen Feng; Hade, Erinn M.; Young, Donn C.; Byrd, John C.; Grever, Michael; Johnson, Kara; Druker, Brian; Chen, Ching Shih.

In: Blood, Vol. 105, No. 10, 15.05.2005, p. 4021-4027.

Research output: Contribution to journalArticle

Tseng, Ping Hui ; Lin, Ho Pi ; Zhu, Jiuxiang ; Chen, Kuen Feng ; Hade, Erinn M. ; Young, Donn C. ; Byrd, John C. ; Grever, Michael ; Johnson, Kara ; Druker, Brian ; Chen, Ching Shih. / Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance. In: Blood. 2005 ; Vol. 105, No. 10. pp. 4021-4027.
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abstract = "Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210 T3151. The 50{\%} inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210E255K and Ba/F3p210T3151 were 14 ± 4 and 30 ± 2 μM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 μM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.",
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AU - Tseng, Ping Hui

AU - Lin, Ho Pi

AU - Zhu, Jiuxiang

AU - Chen, Kuen Feng

AU - Hade, Erinn M.

AU - Young, Donn C.

AU - Byrd, John C.

AU - Grever, Michael

AU - Johnson, Kara

AU - Druker, Brian

AU - Chen, Ching Shih

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N2 - Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210 T3151. The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210E255K and Ba/F3p210T3151 were 14 ± 4 and 30 ± 2 μM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 μM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.

AB - Resistance to the Ableson protein tyrosine (Abl) kinase inhibitor imatinib mesylate has become a critical issue for patients in advanced phases of chronic myelogenous leukemia. Imatinib-resistant tumor cells develop, in part, as a result of point mutations within the Abl kinase domain. As protein kinase B (Akt) plays a pivotal role in Abl oncogene-mediated cell survival, we hypothesize that concurrent inhibition of Akt will sensitize resistant cells to the residual apoptotic activity of imatinib mesylate, thereby overcoming the resistance. Here, we examined the effect of OSU-03012, a celecoxib-derived phosphoinositide-dependent kinase-1 (PDK-1) inhibitor, on imatinib mesylate-induced apoptosis in 2 clinically relevant breakpoint cluster region (Bcr)-Abl mutant cell lines, Ba/F3p210E255K and Ba/F3p210 T3151. The 50% inhibitory concentration (IC50) values of imatinib mesylate to inhibit the proliferation of Ba/F3p210E255K and Ba/F3p210T3151 were 14 ± 4 and 30 ± 2 μM, respectively. There was no cross-resistance to OSU-03012 in these mutant cells with an IC50 of 5 μM irrespective of mutations. Nevertheless, in the presence of OSU-03012 the susceptibility of these mutant cells to imatinib-induced apoptosis was significantly enhanced. This synergistic action was, at least in part, mediated through the concerted effect on phospho-Akt. Together these data provide a novel therapeutic strategy to overcome imatinib mesylate resistance, especially with the Abl mutant T315I.

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