NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor.

The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor.

Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.

Unlabelled: Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor.

Adventitial endothelial implants reduce matrix metalloproteinase-2 expression and increase luminal diameter in porcine arteriovenous grafts.

Objective: Vascular access dysfunction is a major problem in hemodialysis patients. Only 50% of arteriovenous grafts (AVGs) will remain patent 1 year after surgery. AVGs frequently develop stenoses and occlusions at the venous anastomoses in the venous outflow tract.

Laminin modulates morphogenic properties of the collagen XVIII endostatin domain.

We have shown previously that the oligomeric endostatin domain of collagen XVIII (NC1) functioned as a motility-inducing factor regulating the extracellular matrix-dependent morphogenesis of endothelial cells. This motogenic activity gave rise to structures resembling filipodia and lamellipodia and was dependent on Rac, Cdc42, and mitogen-activated protein kinase. Here, we demonstrate that these properties of endostatin are primarily mediated by laminin in the basement membrane and heparan sulfates on the cell surface.

Transcriptional regulation of myeloid differentiation primary response (MyD) genes during myeloid differentiation is mediated by nuclear factor Y.

To understand the molecular mechanism by which interleukin-6 (IL-6) regulates myeloid differentiation primary response (MyD) genes at the onset of M1 myeloid differentiation, we used JunB as a representative MyD gene to isolate and characterize IL-6 responsive elements. An IL-6 responsive element was localized between -65 and -52 of the JunB promoter (-65/-52 IL-6RE). By using antibody and oligonucleotide competition assays in electrophoretic mobility shift assay experiments, we have shown that the heterotrimeric transcription nuclear factor Y (NF-Y) complex binds to this element.

Interleukin-6 and leukemia inhibitory factor induction of JunB is regulated by distinct cell type-specific cis-acting elements.

Interleukin (IL)-6 plays an important role in a wide range of biological activities, including differentiation of murine M1 myeloid leukemic cells into mature macrophages. At the onset of M1 differentiation, a set of myeloid differentiation primary response (MyD) genes are induced, including the proto-oncogene for JunB. In order to examine the molecular nature of the mechanisms by which IL-6 activates the immediate early expression of MyD genes, JunB was used as a paradigm.

Role of a mutant p53 protein in apoptosis: characterization of a function independent of transcriptional trans-activation.

Wild-type (wt) tumor suppressor p53 has been implicated in cellular radiosensitivity, mediated by its role in apoptosis and growth arrest. Intriguingly, it was observed that the temperature sensitive (ts) mutant p53val135 protein functions as a positive modulator of cellular radiosensitivity, as evident from acceleration of irradiation-induced apoptosis of M1p53ts (p53val135) cells at the non-permissive temperature; this effect was correlated with acceleration of exit from the G2 checkpoint of the cell cycle. In this work it is shown that the ability of mutant p53val135 to accelerate irradiation-induced apoptosis, at the non-permissive temperature, was devoid of transcriptional trans-activation of p53 target genes.

The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells.

Cell numbers are regulated by a balance among proliferation, growth arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta 1 (TGF beta 1)-treated M1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected.