dinaciclib and Lung-Neoplasms

Dinaciclib (MK-7965, formerly SCH 727965), a novel, small-molecule inhibitor of cyclin-dependent kinases, has been shown to induce apoptosis in preclinical studies of human tumor cell lines, including non-small cell lung cancer (NSCLC) cells. Erlotinib, an epidermal growth factor receptor inhibitor, is approved for the treatment of advanced NSCLC as second- or third-line therapy. This phase 2, randomized, multicenter, open-label study compared dinaciclib with erlotinib in patients with previously treated NSCLC.. The study was comprised of 2 parts: in part 1, patients were randomized to either intravenous (IV) dinaciclib (50 mg/m2) or oral erlotinib (150 mg) using an adaptive Bayesian design that adjusted the randomization ratio in favor of the more active arm, and in part 2, patients who had progressed on erlotinib were permitted to cross over to receive dinaciclib at the same dosage as in part 1. Patients were followed until disease progression or death, initiation of nonstudy cancer treatment, discontinuation, or withdrawal of consent. The primary efficacy end point was time-to-progression (TTP) in part 1 and objective response rate (ORR) in part 2.. Based on Kaplan-Meier estimates, the median TTP was 1.49 months (95% confidence interval [CI]: 1.31, 2.63) following initial treatment with dinaciclib, compared with 1.58 months (95% CI: 1.38, 2.83) with erlotinib. No objective responses were observed following initial treatment with dinaciclib. Common severe (grade 3 or 4) drug-related adverse effects included neutropenia, leukopenia, vomiting, and diarrhea.. Dinaciclib, administered IV, was well tolerated at the 50 mg/m2 dose, but does not have activity as monotherapy in previously treated NSCLC. Evaluation of dinaciclib in combination with other agents for other indications including breast cancer and multiple myeloma is in progress.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cyclic N-Oxides; Cyclin-Dependent Kinases; Disease-Free Survival; ErbB Receptors; Erlotinib Hydrochloride; Female; Follow-Up Studies; Humans; Indolizines; Injections, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neutropenia; Pyridinium Compounds; Quinazolines

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor-induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or in combination with taxanes. Mol Cancer Ther; 15(11); 2758-66. ©2016 AACR.

Topics: Anaphase; Animals; Bridged Bicyclo Compounds, Heterocyclic; CDC2 Protein Kinase; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Drug Resistance, Neoplasm; Humans; Indolizines; Lung Neoplasms; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Mutation; Phosphoproteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridinium Compounds; Taxoids