MCL1 and BCL-xL levels in solid tumors are predictive of dinaciclib-induced apoptosis
| Autor: | Mark Ayers, Brian Long, Rebecca L. Blanchard, Andrey Loboda, Eun Kyung Im, Gary Gilliland, Nathan R. Miselis, Minilik Angagaw, Junghoon Lee, Vincenzo Pucci, Anna Georgieva Kondic, Alwin Schuller, Yaolin Wang, Carrie E. Merkel, Brian Dolinski, Peter Strack, Lauren Harmonay, Theresa Zhang, Michael Nebozhyn, Xianlu Q. Lennon, Ali-Samer Al-Assaad, James W. Monahan, Bin Shi, Harold Hatch, Leigh Zawel, David J. Mauro, Heather Hirsch, Robert Booher, Stephen Fawell, Thi D.T. Nguyen |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cell cycle checkpoint Gene Dosage Cancer Treatment lcsh:Medicine Apoptosis Pyridinium Compounds Pharmacology Mice chemistry.chemical_compound Neoplasms Basic Cancer Research Drug Discovery Medicine and Health Sciences MCL1 Cell Cycle and Cell Division lcsh:Science Sulfonamides Aniline Compounds Cancer Drug Discovery Multidisciplinary Navitoclax Cell Death Indolizines Drug Synergism Oncology Cell Processes Female Oncology Agents Antiangiogenesis Therapy Diterpenes Research Article Drug Research and Development bcl-X Protein Antineoplastic Agents Bcl-xL Biology Cyclic N-Oxides In vivo Cell Line Tumor Animals Humans RNA Messenger Dinaciclib Cell Cycle Inhibitors Cyclin-dependent kinase 1 lcsh:R Biology and Life Sciences Cell Cycle Checkpoints Cell Biology Phenanthrenes Bridged Bicyclo Compounds Heterocyclic Xenograft Model Antitumor Assays Disease Models Animal Pharmacodynamics chemistry Drug Resistance Neoplasm biology.protein Epoxy Compounds Myeloid Cell Leukemia Sequence 1 Protein lcsh:Q |
| Zdroj: | PLoS ONE, Vol 9, Iss 10, p e108371 (2014) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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