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.
MeSH terms
-
Adenocarcinoma of Lung / drug therapy
-
Adenocarcinoma of Lung / genetics
-
Adenocarcinoma of Lung / metabolism
-
Adenocarcinoma of Lung / pathology
-
Animals
-
Antineoplastic Agents / pharmacology
-
Apoptosis / drug effects
-
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
-
Ataxia Telangiectasia Mutated Proteins / genetics*
-
Ataxia Telangiectasia Mutated Proteins / metabolism
-
Benzodiazepinones / pharmacology*
-
Cell Cycle / drug effects
-
Cell Cycle / genetics
-
Cell Line, Tumor
-
Checkpoint Kinase 1 / antagonists & inhibitors
-
Checkpoint Kinase 1 / genetics*
-
Checkpoint Kinase 1 / metabolism
-
DNA Damage
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics
-
Gene Expression Regulation, Neoplastic*
-
Humans
-
Isoxazoles / pharmacology*
-
Lung Neoplasms / drug therapy*
-
Lung Neoplasms / genetics
-
Lung Neoplasms / metabolism
-
Lung Neoplasms / pathology
-
Male
-
Mice
-
Mice, Nude
-
Molecular Targeted Therapy
-
Protein Kinase Inhibitors / pharmacology
-
Proto-Oncogene Proteins p21(ras) / genetics
-
Proto-Oncogene Proteins p21(ras) / metabolism
-
Pyrazines / pharmacology*
-
Pyrazoles / pharmacology*
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Signal Transduction
-
Small Cell Lung Carcinoma / drug therapy*
-
Small Cell Lung Carcinoma / genetics
-
Small Cell Lung Carcinoma / metabolism
-
Small Cell Lung Carcinoma / pathology
-
Xenograft Model Antitumor Assays
-
cdc25 Phosphatases / genetics
-
cdc25 Phosphatases / metabolism
Substances
-
Antineoplastic Agents
-
Benzodiazepinones
-
Isoxazoles
-
KRAS protein, human
-
PF 00477736
-
Protein Kinase Inhibitors
-
Pyrazines
-
Pyrazoles
-
RNA, Messenger
-
ATR protein, human
-
Ataxia Telangiectasia Mutated Proteins
-
CHEK1 protein, human
-
Checkpoint Kinase 1
-
CDC25A protein, human
-
CDC25B protein, human
-
CDC25C protein, human
-
cdc25 Phosphatases
-
Proto-Oncogene Proteins p21(ras)
-
berzosertib