Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer

Autor:	Reinhard Büttner, Maike Wittersheim, Sarah Hermann, Anna Schmitt, Filippo Beleggia, Roman K. Thomas, Jean Philip Weber, Vonn Walter, Julie George, Thorsten Persigehl, Fabian Doerr, H. Christian Reinhardt, Tim Rehkämper
Jazyk:	angličtina
Rok vydání:	2017
Předmět:	Male 0301 basic medicine Lung Neoplasms Cell cycle checkpoint lcsh:Medicine Apoptosis Ataxia Telangiectasia Mutated Proteins medicine.disease_cause Mice Molecular Targeted Therapy lcsh:Science Benzodiazepinones Multidisciplinary Cell Cycle Cell cycle humanities Gene Expression Regulation Neoplastic Pyrazines Adenocarcinoma KRAS biological phenomena cell phenomena and immunity Signal Transduction CDC25A Mice Nude Adenocarcinoma of Lung Antineoplastic Agents Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Cell Line Tumor medicine Animals Humans cdc25 Phosphatases RNA Messenger CHEK1 Lung cancer Protein Kinase Inhibitors neoplasms business.industry lcsh:R Isoxazoles medicine.disease Small Cell Lung Carcinoma Xenograft Model Antitumor Assays respiratory tract diseases 030104 developmental biology Drug Resistance Neoplasm Checkpoint Kinase 1 Cancer research Pyrazoles lcsh:Q business DNA Damage
Zdroj:	Scientific Reports, Vol 7, Iss 1, Pp 1-16 (2017) Scientific Reports
ISSN:	2045-2322
Popis:	Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma. In line with uncontrolled cell cycle progression in SCLC, we find that CDC25A, B and C mRNAs are expressed at significantly higher levels in SCLC, compared to lung adenocarcinoma. We next profiled the efficacy of compounds targeting CHK1 and ATR. Both, ATR- and CHK1 inhibitors induce genotoxic damage and apoptosis in human and murine SCLC cell lines, but not in lung adenocarcinoma cells. We further demonstrate that murine SCLC tumors were highly sensitive to ATR- and CHK1 inhibitors, while Kras G12D -driven murine lung adenocarcinomas were resistant against these compounds and displayed continued growth under therapy. Altogether, our data indicate that SCLC displays an actionable dependence on ATR/CHK1-mediated cell cycle checkpoints.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e9ad0d9ed388dd9d99340020975dd1d8 http://link.springer.com/article/10.1038/s41598-017-15840-5 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.