Pulmonary Cell News Volume 7.47 | Nov 29 2018

TOP STORY

Aurora Kinase A Drives the Evolution of Resistance to Third-Generation EGFR Inhibitors in Lung Cancer

Nongenetic resistance through the activation of aurora kinase A (AURKA) by its coactivator TPX2 emerged in response to chronic epidermal growth factor receptor (EGFR) inhibition where it mitigated drug-induced apoptosis. Treatment-induced activation of AURKA was associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. [Nat Med] Abstract | Press Release | Editorial

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IL-13 Signaling through IL-13 Receptor α2 Mediates Airway Epithelial Wound Repair

The blocking of IL-13 signaling via IL-13Rα2 significantly reduced airway epithelial repair by 24 hour post-mechanical wounding in 1HAEo⁻ cells. Expression and release of repair-mediating growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor, and subsequent activation of EGF receptor were also significantly reduced in response to wounding when IL-13Rα2 was blocked. [FASEB J] Abstract

Aflatoxin G₁ Induced TNF-α-Dependent Lung Inflammation to Enhance DNA Damage in Alveolar Epithelial Cells

The authors treated primary mice AT-II cells and human AT-II like cells (A549) with aflatoxin G₁ (AFG₁) and TNF-α and found that TNF-α enhanced the AFG₁-induced DNA damage in mice AT-II cells as well as A549 cells in vitro. In AFG₁-exposed A549 cells, TNF-α-enhanced DNA damage and apoptosis were reversed by CYP2A13 small interfering RNA. [J Cell Physiol] Abstract

Vitamin D Attenuates Rhinovirus-Induced Expression of Intercellular Adhesion Molecule-1 (ICAM-1) and Platelet-Activating Factor Receptor (PAFR) in Respiratory Epithelial Cells

Researchers characterized the influence of the major circulating metabolite 25-hydroxyvitamin D (25[OH]D) and the active metabolite 1,25[OH]₂D on responses of a respiratory epithelial cell line to infection with a major group human rhinovirus. [J Steroid Biochem Mol Biol] Abstract

Ambient Fine Particulate Matter Induce Toxicity in Lung Epithelial-Endothelial Co-Culture Models

The transwell culture method was used to establish bi-culture consisting of A549 alveolar epithelial cells monoculture in apical chamber and EA.hy 926 endothelial cells in the basolateral chamber, while tri-culture systems consisting of co-culture in the apical chamber and also EA.hy 926 endothelial cells in the basolateral chamber. [Toxicol Lett] Abstract

LUNG CANCER

Compound Haploinsufficiency of Dok2 and Dusp4 Promotes Lung Tumorigenesis

By targeting the mouse orthologs of human Dok2 and Dusp4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, investigators found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. [J Clin Invest] Full Article

Cancer-Associated Fibroblasts Suppress SOX2-Induced Dysplasia in a Lung Squamous Cancer Coculture

Scientists report the establishment of a 3D coculture system of lung squamous carcinoma epithelial cells with cancer-associated fibroblasts and extracellular matrix that together capture key components of the tumor microenvironment. [Proc Natl Acad Sci USA] Full Article

Hyperactivation of ERK by Multiple Mechanisms Is Toxic to RTK-RAS Mutation-Driven Lung Adenocarcinoma Cells

A dual specificity phosphatase, DUSP6, that negatively regulates phosphorylation of extracellular signal-regulated kinase was up-regulated in EGFR- or KRAS-mutant lung adenocarcinoma, potentially protecting cells with mutations in the RAS signaling pathway, a proposal supported by experiments with DUSP6-specific siRNA and an inhibitory drug. [eLIFE] Full Article

The Risk Variant rs884225 within EGFR Impairs miR-103a-3p’s Anti-Tumourigenic Function in Non-Small Cell Lung Cancer

miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer cell lines, respectively, which substantially reduced EGFR expression and activity. [Oncogene] Abstract

The Long Noncoding RNA LINC00312 Induces Lung Adenocarcinoma Migration and Vasculogenic Mimicry through Directly Binding YBX1

Investigators found that LINC00312 induced migration, invasion and vasculogenic mimicry of lung cancer cells by direct binding to the transcription factor Y-box binding protein 1 (YBX1). Moreover, they demonstrated that YBX1 was associated with different fragments within 0–2410 nt 5’region of LINC00312. [Mol Cancer] Full Article

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RNA Is Taking Its Toll – Impact of RNA-Specific Toll-Like Receptors on Health and Disease

RNA-sensing toll-like receptors are often described as anti-viral receptors of the innate immune system. However, the past decade has shown that the function and importance of these receptors is far more complex. [Allergy] Abstract | Full Article

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European Commission Approves ALUNBRIG^® (Brigatinib) for ALK⁺ Non-Small Cell Lung Cancer in Patients Previously Treated with Crizotinib, Advancing Treatment Paradigm in Europe

Takeda Pharmaceutical Company Limited announced that the European Commission granted marketing authorization for ALUNBRIG as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase-positive (ALK⁺) advanced non-small cell lung cancer previously treated with crizotinib. [Takeda Pharmaceutical Company Limited] Press Release

Vertex Announces European Commission Approval for KALYDECO^® (Ivacaftor) to Treat Patients with Cystic Fibrosis Aged 12 to <24 Months with Certain Mutations in the CFTR Gene

The label update is based on data from the ongoing Phase III open-label safety study of children with cystic fibrosis aged 12 to <24 months who have one of 10 mutations in the CFTR gene that demonstrated a safety profile consistent with that observed in previous Phase III studies of older children and adults, and improvements in sweat chloride, a key secondary efficacy endpoint. [Vertex Pharmaceuticals Incorporated] Press Release

Vectura Announces Results for Late Stage Clinical Asset VR475 in Severe Uncontrolled Asthma

Vectura Group plc announced that its Phase III study of VR475 in adult and adolescent patients with severe uncontrolled asthma did not meet its primary endpoint. VR475 is a drug device combination consisting of budesonide delivered by Vectura’s proprietary nebuliser inhalation system. [Vectura Group plc] Press Release

G1 Therapeutics Announces Positive Myelopreservation Data from Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Trilaciclib in Combination with Chemotherapy/Tecentriq^® in First-Line Small Cell Lung Cancer

G1 Therapeutics, Inc. announced positive topline data from its randomized, double-blind, placebo-controlled Phase II trial evaluating trilaciclib in combination with chemotherapy and the checkpoint inhibitor Tecentriq^® as a treatment for first-line small cell lung cancer. [G1 Therapeutics, Inc.] Press Release

PhaseBio Announces Dosing of First Patient in Phase IIb Clinical Trial of PB1046 in Pulmonary Arterial Hypertension

The trial will evaluate the effects of PB1046 on pulmonary hemodynamics and exercise tolerance as measured by the six-minute walk test, an important clinical endpoint that the FDA has used as the basis for approval of other pulmonary arterial hypertension drugs. [PhaseBio Pharmaceuticals, Inc.] Press Release

Biomarck Announces It Has Completed Enrollment in the Phase II Controlled Clinical Study in Non Small Cell Lung Cancer (NSCLC)

Biomarck Pharmaceuticals, Ltd announced that it has completed enrollment in the Phase II study in NSCLC. This study compares standard of care, (SOC) to SOC plus BIO-11006 in 60 patients with stage 4, NSCLC. [Biomarck Pharmaceuticals, Ltd (PR Newswire Association LLC.)] Press Release

Asterias Biotherapeutics Announces Fourth Patient Dosed in First-in-Human Clinical Study of Immunotherapy VAC2 in Non-Small Cell Lung Cancer

Asterias Biotherapeutics, Inc. announced enrollment and dosing of the fourth subject in the first-in-human Phase I clinical trial of VAC2 in the United Kingdom. This initial clinical trial, which is being sponsored, managed and funded by Cancer Research UK, will examine the safety and tolerability of VAC2 in non-small cell lung cancer as the study’s primary endpoints. [Asterias Biotherapeutics, Inc.] Press Release

Theravance Biopharma Announces First Subject Dosed in Phase I Clinical Trial of TD-8236, a Novel Inhaled Pan-JAK Inhibitor

Theravance Biopharma, Inc. announced dosing of the first subject in a Phase I clinical trial of TD-8236, a novel, inhaled, lung-selective pan-Janus kinase (JAK) inhibitor which has demonstrated potency in preclinical assessments. [Theravance Biopharma] Press Release

Bristol-Myers Squibb Announces CheckMate -451 Study Did Not Meet Primary Endpoint of Overall Survival with Opdivo plus Yervoy vs. Placebo as a Maintenance Therapy in Patients with Extensive-Stage Small Cell Lung Cancer after Completion of First-Line

No new safety signals were observed with Opdivo 1 mg/kg plus Yervoy 3 mg/kg in this study. The company will work with study investigators on the future publication of these results. [Bristol-Myers Squibb] Press Release

China Halts Genome Editing Research That Led to Claimed Birth of CRISPR Babies

The Chinese government said it had halted research that allegedly led to the births of the world’s first gene-edited babies, as the organizers of an international summit on human genome editing made clear that such research should not have been done and that, for now, similar attempts should not be made. [STAT News] Editorial

Does Science Have a Bullying Problem?

A spate of bullying allegations have rocked several high-profile science institutions. Here’s how researchers, universities, funders and others are dealing with the issue. [Nature News] Editorial

NEW 16^th ECFS Basic Science Conference
March 27-30, 2019
Dubrovnik, Croatia

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NEW Postdoctoral Researcher – Lung Cancer Research (University of Cologne)

Research Associate – Gene Therapy Lung Research (Imperial College of London)

Postdoctoral Position – Pulmonary Fibrosis Research (University of California San Francisco)

Staff Scientist/ Tier 2 Canada Research Chair – Lung Research (University of Toronto)

Faculty Positions – Cancer-Focused Target & Drug Discovery (University of New Mexico)

Postdoctoral Research Fellow – Sepsis & Lung Inflammation Pathogenesis Research (Boston University)

Associate Professor – Oncology (University of California, Davis)

Postdoctoral Scholar – Cancer Metabolism (The Moffitt Cancer Center)

Postdoctoral Position – Lung Cancer Biology (UT Southwestern Medical Center)

Postdoctoral Research Scientist – Modeling Infection in Human Lung Organoids (Columbia University)

Postdoctoral Position – Human Lung Organoid Research (Columbia University Medical Center)

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