Abstract
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Apoptosis / genetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cyclic N-Oxides
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Disease Models, Animal
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Diterpenes / pharmacology
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Drug Resistance, Neoplasm / genetics
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Drug Synergism
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Epoxy Compounds / pharmacology
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Female
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Gene Dosage
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Humans
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Indolizines
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Male
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism*
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Phenanthrenes / pharmacology
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Pyridinium Compounds / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sulfonamides / pharmacology
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Xenograft Model Antitumor Assays
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Aniline Compounds
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclic N-Oxides
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Diterpenes
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Epoxy Compounds
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Indolizines
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Phenanthrenes
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Pyridinium Compounds
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RNA, Messenger
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Sulfonamides
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bcl-X Protein
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triptolide
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dinaciclib
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navitoclax
Grants and funding
Merck provided all funds for this work. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no current external support or funding to report.