Reference Detail

Ref Type

Journal Article

PMID

(29138515)

Authors

Doerr F, George J, Schmitt A, Beleggia F, Rehkämper T, Hermann S, Walter V, Weber JP, Thomas RK, Wittersheim M, Büttner R, Persigehl T, Reinhardt HC

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	7	1	2017 Nov 14	15511	Sci Rep

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CHEK1 over exp	lung small cell carcinoma	sensitive	Berzosertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, small cell lung cancer cell lines, which expressed high levels of CHEK1, demonstrated sensitivity to Berzosertib (VX-970) treatment, resulting in decreased viability in culture and reduced tumor growth in xenograft models (PMID: 29138515).	29138515
CHEK1 over exp	lung small cell carcinoma	sensitive	PF-00477736	Preclinical - Cell line xenograft	Actionable	In a preclinical study, small cell lung cancer cell lines, which expressed high levels of CHEK1, demonstrated sensitivity to PF-00477736 treatment, resulting in decreased viability in culture and reduced tumor growth in xenograft models (PMID: 29138515).	29138515