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

• Published in: Cancer biology & therapy Vol. 16; no. 12; pp. 1784 - 1793
• Main Authors: Qi, Wenxiu, Zhang, Wenbo, Edwards, Holly, Chu, Roland, Madlambayan, Gerard J, Taub, Jeffrey W, Wang, Zhihong, Wang, Yue, Li, Chunhuai, Lin, Hai, Ge, Yubin
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.12.2015
• Subjects: Acute myeloid leukemia; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Checkpoint Kinase 1; CHK1; Drug Synergism; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Indoles - pharmacology; Inhibitory Concentration 50; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; MK-1775; Nuclear Proteins - antagonists & inhibitors; Panobinostat; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Research Paper; Wee1; Panobinostat; Wee1; CHK1; Acute myeloid leukemia; MK-1775
• ISSN: 1538-4047; 1555-8576
• DOI: 10.1080/15384047.2015.1095406

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.