dinaciclib and Disease-Models--Animal

Topics: Animals; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclic N-Oxides; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunomodulation; Immunophenotyping; Indolizines; Killer Cells, Natural; Leukemia, Myeloid, Acute; Lymphocyte Activation; Mice; Protein Kinase Inhibitors; Pyridinium Compounds; Xenograft Model Antitumor Assays

Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775.. Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines.. Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Cell Line, Tumor; Cyclic N-Oxides; Cyclin E; Disease Models, Animal; DNA Repair; DNA Replication; Drug Resistance, Neoplasm; Gene Expression; Humans; Indolizines; Mice; Mice, Knockout; Models, Biological; Nuclear Proteins; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridinium Compounds; Pyrimidinones; Stress, Physiological; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease of the blood affecting children, adolescents and adults. Although current treatment protocols for T-ALL have improved overall survival, a portion of T-ALL patients still experiences treatment failure. Thus, the development of novel therapies is needed. In this study, we used several patient-derived T-ALL cell lines to screen for an effective drug for T-ALL. Using a panel of 378 inhibitors against different kinases, we identified the CDK inhibitor dinaciclib as a potential drug for T-ALL. Dinaciclib treatment significantly reduced cell viability and completely blocked colony formation. Furthermore, cells treated with dinaciclib showed decreased expression of several pro-survival proteins including survivin, cyclin T1 and c-MYC. Dinaciclib treatment also increased accumulation of cells in G2/M phase and significantly induced apoptosis. Finally, dinaciclib extended survival of mice in a T-ALL cell xenograft model. Collectively, these data suggest that the CDK inhibitor dinaciclib is an active drug for T-ALL in the preclinical settings.

Topics: Adult; Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic N-Oxides; Cyclin-Dependent Kinases; Disease Models, Animal; Humans; Indolizines; Mice; Molecular Targeted Therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyridinium Compounds

Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is responsible for approximately 15% of cancer-related mortality in children. Aberrant activation of cyclin-dependent kinases (CDKs) has been shown to contribute to tumor cell progression in many cancers including NB. Therefore, small molecule inhibitors of CDKs comprise a strategic option in cancer therapy. Here we show that a novel multiple-CDK inhibitor, dinaciclib (SCH727965, MK-7965), exhibits potent anti-proliferative effects on a panel of NB cell lines by blocking the activity of CDK2 and CDK9. Dinaciclib also significantly sensitized NB cell lines to the treatment of chemotherapeutic agents such as doxorubicin (Dox) and etoposide (VP-16). Furthermore, dinaciclib revealed in vivo antitumor efficacy in an orthotopic xenograft mouse model of two NB cell lines and blocked tumor development in the TH-MYCN transgenic NB mouse model. Taken together, this study suggests that CDK2 and CDK9 are potential therapeutic targets in NB and that abrogating CDK2 and CDK9 activity by small molecules like dinaciclib is a promising strategy and a treatment option for NB patients.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 9; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Humans; Indolizines; Mice; Neuroblastoma; Phosphorylation; Protein Kinase Inhibitors; Pyridinium Compounds; Signal Transduction; Xenograft Model Antitumor Assays

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.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclic N-Oxides; Disease Models, Animal; Diterpenes; Drug Resistance, Neoplasm; Drug Synergism; Epoxy Compounds; Female; Gene Dosage; Humans; Indolizines; Male; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Phenanthrenes; Pyridinium Compounds; RNA, Messenger; Sulfonamides; Xenograft Model Antitumor Assays