Universität zu Köln

Doerr, Fabian, George, Julie, Schmitt, Anna, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Rehkaemper, Tim, Hermann, Sarah, Walter, Vonn ORCID: 0000-0001-6114-6714, Weber, Jean-Philip, Thomas, Roman K., Wittersheim, Maike, Buettner, Reinhard, Persigehl, Thorsten and Reinhardt, H. Christian (2017). Targeting a non-oncogene addiction to the ATR/CHK1 axis for the treatment of small cell lung cancer. Sci Rep, 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Doerr, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED George, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitt, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Rehkaemper, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermann, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Walter, Vonn UNSPECIFIED orcid.org/0000-0001-6114-6714 UNSPECIFIED Weber, Jean-Philip UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Roman K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittersheim, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Persigehl, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-211265
DOI:	10.1038/s41598-017-15840-5
Journal or Publication Title:	Sci Rep
Volume:	7
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2045-2322
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; THERAPEUTIC TARGET; PHASE-II; CHECKPOINT; ATR; CHK1; INHIBITORS; PATHWAY; CYCLE; ADENOCARCINOMA Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21126