Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo
Wenxiu Qi1, Wenbo Zhang1, Holly Edwards2,3
1a National Engineering Laboratory for AIDS Vaccine; Key Laboratory for Molecular Enzymology and Engineering; the Ministry of Education; School of Life Sciences; Jilin University ; Changchun , China.
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.
Insights
Panobinostat combined with MK-1775 shows synergistic effects in acute myeloid leukemia (AML) by inducing cell death and proliferation arrest. This combination therapy targets Wee1 and CHK1 pathways, offering a promising new treatment for AML.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Acute myeloid leukemia (AML) remains a significant clinical challenge requiring novel therapeutic strategies.
- MK-1775, a selective Wee1 inhibitor, has shown synergy with CHK1 inhibitors in various cancers.
- Pan-histone deacetylase inhibitors (HDACls) represent a class of drugs with potential anti-cancer activity.
Purpose of the Study:
- To investigate the synergistic potential of panobinostat (an HDACI) and MK-1775 in acute myeloid leukemia (AML).
- To elucidate the underlying molecular mechanisms of this drug combination in AML cells.
Main Methods:
- Utilized AML cell line models and primary patient samples.
- Assessed synergistic effects on proliferation and cell death.
- Investigated changes in Wee1 and CHK1 pathway protein levels.
- Employed shRNA knockdown techniques for CHK1 and Wee1.
Main Results:
- Panobinostat and MK-1775 synergistically induced proliferation arrest and cell death in AML models.
- Panobinostat demonstrated anti-leukemic activity against both newly diagnosed and relapsed AML.
- The combination treatment led to decreased Wee1 protein levels and CHK1 pathway downregulation.
- Knockdown of CHK1 sensitized cells to MK-1775, while Wee1 knockdown enhanced cell death induced by both drugs.
Conclusions:
- Panobinostat synergizes with MK-1775 in AML, offering a potential new therapeutic approach.
- The synergy is, in part, mediated by the downregulation of CHK1 and/or Wee1 pathways.
- This combination warrants further clinical development for the treatment of AML.
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