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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.
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