Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells

Tri Nguyen; Elisa Hawkins; Akhil Kolluri; Maciej Kmieciak; Haeseong Park; Hui Lin; Steven Grant

doi:10.1016/j.leukres.2014.10.009

Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells

Tri Nguyen, Elisa Hawkins, Akhil Kolluri, Maciej Kmieciak, Haeseong Park, Hui Lin, Steven Grant

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL⁺ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph⁺ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34⁺ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34⁺ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph⁺ ALL.

Original language	English
Pages (from-to)	65-71
Number of pages	7
Journal	Leukemia Research
Volume	39
Issue number	1
DOIs	https://doi.org/10.1016/j.leukres.2014.10.009
State	Published - Jan 1 2015

Keywords

BCR/ABL
Bosutinib
Chk1 inhibitor
Chronic myeloid leukemia

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10.1016/j.leukres.2014.10.009

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title = "Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells",

abstract = "Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL+ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph+ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34+ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34+ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph+ ALL.",

keywords = "BCR/ABL, Bosutinib, Chk1 inhibitor, Chronic myeloid leukemia",

author = "Tri Nguyen and Elisa Hawkins and Akhil Kolluri and Maciej Kmieciak and Haeseong Park and Hui Lin and Steven Grant",

note = "Funding Information: This study is supported by award RO1 CA100866, P50 CA142509, RO1 CA167708, P30 CA16059 from the NIH (S. Grant) and award 6238-12 from the Leukemia and Lymphoma Society of America (T. Nguyen and S. Grant). Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd.",

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AU - Nguyen, Tri

AU - Hawkins, Elisa

AU - Kolluri, Akhil

AU - Kmieciak, Maciej

AU - Park, Haeseong

AU - Lin, Hui

AU - Grant, Steven

N1 - Funding Information: This study is supported by award RO1 CA100866, P50 CA142509, RO1 CA167708, P30 CA16059 from the NIH (S. Grant) and award 6238-12 from the Leukemia and Lymphoma Society of America (T. Nguyen and S. Grant). Publisher Copyright: © 2014 Elsevier Ltd.

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N2 - Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL+ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph+ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34+ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34+ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph+ ALL.

AB - Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL+ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph+ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34+ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34+ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph+ ALL.

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Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells

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