Small cell lung cancer (SCLC) is a difcult 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 signifcant overexpression of genes involved in the DNA damage response, specifcally in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is signifcantly overexpressed in SCLC, compared to lung adenocarcinoma. In line with uncontrolled cell cycle progression in SCLC, we fnd that CDC25A, B and C mRNAs are expressed at signifcantly higher levels in SCLC, compared to lung adenocarcinoma. We next profled the efcacy 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 KrasG12D-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.
All Science Journal Classification (ASJC) codes