Checkpoint Inhibition Leads to a Reduction of Small Cell Lung Cancer Tumor Growth

Objectives: Small cell lung cancer is characterized by its extraordinary aggressiveness and early dissemination. As a result, only 5% of all patients can be surgically treated. By using two different check-point inhibitors in in vitro and in vivo experiments, we tested their capacity to reduce tumor volume.

Methods: The CHEK1-Gen was targeted with a Chk1-inhibitor and an upstream acting ATR-inhibitor. We profiled the efficacy and sensitivity of both inhibitors in murine small cell lung cancer cells and performed a validation of the in vitro findings in three different mouse-models (allograft, autochthonous and xenograft). Tumor volume was monitored by µCT imaging, MRI scans and digital caliper measurements.

Results: Murine small cell lung cancer cell lines were sensitive to ATR- and CHK1 inhibition in cell viability assay and flow cytometry experiments. The GI50 values of ATR were 1.9 µMol and of CHK1 were 1.7 µMol. Both inhibitors induced significant genotoxic damage in immunofluorescence and immunoblotting experiments. Tumor shrinkage in the allograft model (ATR: p = 0.0001; CHK1: p < 0.0001) led to significant survival benefit (untreated: 66 days; ATR: 133 days; CHK1: 144 days; p < 0.0008). CHK1-inhibition resulted in significant tumor reduction and a 60-day survival benefit (p = 0.0286) in the autochthonous model. Human small cell lung cancer cells showed a high sensibility to both check-point inhibitors, which significantly delayed tumor growth in the xenograft model.

Conclusion: Small cell lung cancer cells depend on ATR/CHK1-mediated cell cycle check points. The resultant reduction of tumor volume has potential in preoperative down-staging of cancer in a neoadjuvant setting. In future, patients in advanced small cell lung cancer stages might consequently be surgically treated.