The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.

Abstract

Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

• Authors: Adele Baker, Gareth P Gregory, Inge Verbrugge, Lev Kats, Joshua J Hilton, Eva Vidacs, Erwin M Lee, Richard B Lock, Johannes Zuber, Jake Shortt, Ricky W Johnstone
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 5 Pg. 1158-69 (Mar 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26627013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Cyclic N-Oxides
• Hydroxamic Acids
• Indoles
• Indolizines
• KMT2A protein, human
• MLL-AF9 fusion protein, human
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Pyridinium Compounds
• Myeloid-Lymphoid Leukemia Protein
• dinaciclib
• Panobinostat
• Histone-Lysine N-Methyltransferase
• Cyclin-Dependent Kinase 9

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cyclic N-Oxides
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors)
• Drug Resistance, Neoplasm
• Gene Rearrangement
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles (pharmacology)
• Indolizines
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors)
• Myeloid-Lymphoid Leukemia Protein (genetics)
• Oncogene Proteins, Fusion (genetics)
• Panobinostat
• Protein Kinase Inhibitors (pharmacology)
• Pyridinium Compounds (pharmacology)