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

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.

Weighted Gene Coexpression Network Analysis of Features That Control Cancer Stem Cells Reveals Prognostic Biomarkers in Lung Adenocarcinoma

“…In addition, Doerr et al (2017) confirmed that CHEK1 is highly expressed in small-cell lung cancer (SCLC) compared with LUAD. In vivo studies in mice showed that blocking the CHEK1-related pathway can induce genotoxic damage and apoptosis in SCLC cells but not in LUAD (Doerr et al, 2017). However, Yu et al (2012) demonstrated in mice that miR-195 regulates the response of NSCLC cells to microtubule-targeting agents (MTAs) by targeting CHEK1.…”

“…CHEK1 is regarded as a target gene for potential tumor treatment (McNeely et al, 2014). In addition, Doerr et al (2017) confirmed that CHEK1 is highly expressed in small-cell lung cancer (SCLC) compared with LUAD. In vivo studies in mice showed that blocking the CHEK1-related pathway can induce genotoxic damage and apoptosis in SCLC cells but not in LUAD (Doerr et al, 2017).…”

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

“…Indeed, CHK1 inhibitor prexasertib as a single-agent has shown remarkable anti-tumor activity in a preclinical study [21]. A transcriptomic profile found that the expression of CDC25 is much higher in SCLC than that in NSCLC [22]. Pharmacological inhibition of SCLC cells by ATR inhibitor VE-822 and CHK1 inhibitor PF-477736 selectively eliminates SCLC cells, but not NSCLC cells [22].…”

“…A transcriptomic profile found that the expression of CDC25 is much higher in SCLC than that in NSCLC [22]. Pharmacological inhibition of SCLC cells by ATR inhibitor VE-822 and CHK1 inhibitor PF-477736 selectively eliminates SCLC cells, but not NSCLC cells [22]. Additionally, ATR/CHK1 signaling cascade also can be activated by DSB.…”

“…replication stress inducers with other therapeutics have been investigated in preclinical and clinical 56 studies and have shown augmented beneficial effects compared with either agent alone [21][22][23][24]. 57 Causes of replication stress in small cell lung cancer (SCLC) cells.…”