MCL1 and BCL-xL Levels in Solid Tumors Are Predictive of Dinaciclib-Induced Apoptosis

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 year

  2014

• Venue

  PLoS ONE

• Publication date

  2014-10-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0108371PMID 25289887PMCID 4188521
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2012cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2011cited by this paper
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  2010cited by this paper
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  2010cited by this paper
• Aven blocks DNA damage-induced apoptosis by stabilising Bcl-xL.

  2010cited by this paper
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  2010cited by this paper
• Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia.

  2009cited by this paper
• ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.

  2008cited by this paper
• Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models

  2008cited by this paper
• Triptolide-induced transcriptional arrest is associated with changes in nuclear substructure.

  2008cited by this paper
• Chemical combination effects predict connectivity in biological systems

  2007cited by this paper
• Rapid Turnover of Mcl-1 Couples Translation to Cell Survival and Apoptosis*

  2007cited by this paper
• Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737.

  2007cited by this paper
• Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells.

  2006influential reference
• Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death.

  2005cited by this paper
• A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival.

  2005cited by this paper
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  2005cited by this paper
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  2004cited by this paper
• Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

  2004cited by this paper
• Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas apoptosis in Burkitt's lymphomas with loss of multiple pro-apoptotic proteins.

  2003cited by this paper
• Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control

  2002influential reference
• Bax is frequently compromised in Burkitt's lymphomas with irreversible resistance to Fas-induced apoptosis.

  1999cited by this paper
• Hematopoietic malignancies demonstrate loss-of-function mutations of BAX.

  1998cited by this paper
• Association of Cdk-activating kinase subunits with transcription factor TFIIH

  1995cited by this paper
• Developmental regulation of the Bcl‐2 protein and susceptibility to cell death in B lymphocytes.

  1994cited by this paper
• Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells

  1984cited by this paper

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  2023cites this paper
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  2022cites this paper
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  2021cites this paper
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  2020cites this paper
• Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer

  2020influential citation
• CDK12: a potential therapeutic target in cancer.

  2020cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2018cites this paper
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• Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018influential citation
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  2017cites this paper
• Positive transcription elongation factor b (P-TEFb) is a therapeutic target in human multiple myeloma

  2017cites this paper
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  2017cites this paper
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  2017cites this paper
• Genomic profiling of lung adenocarcinoma patients reveals therapeutic targets and confers clinical benefit when standard molecular testing is negative

  2016cites this paper
• Cyclin-dependent kinase inhibitors for the treatment of chronic lymphocytic leukemia.

  2016cites this paper
• Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain.

  2016cites this paper
• Targeting CDK9: a promising therapeutic opportunity in prostate cancer.

  2016cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
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  2015cites this paper
• Modifications of RNA polymerase II CTD: Connections to the histone code and cellular function.

  2015cites this paper
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  2014cites this paper