Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Wenxiu Qi, Wenbo Zhang, Holly Edwards, Roland Chu, Gerard J. Madlambayan, Jeffrey W. Taub, Zhihong Wang, Yue Wang, Chunhuai Li, Hai Lin, Yubin Ge

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

Original languageEnglish
Pages (from-to)1784-1793
Number of pages10
JournalCancer Biology and Therapy
Volume16
Issue number12
DOIs
StatePublished - Dec 2 2015

Keywords

  • Acute myeloid leukemia
  • CHK1
  • MK-1775
  • Panobinostat
  • Wee1

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