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 journalArticlepeer-review

15 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 languageEnglish
Pages (from-to)65-71
Number of pages7
JournalLeukemia Research
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • BCR/ABL
  • Bosutinib
  • Chk1 inhibitor
  • Chronic myeloid leukemia

Fingerprint

Dive into the research topics of 'Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells'. Together they form a unique fingerprint.

Cite this