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Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients
- Source :
- Journal of cancer research and clinical oncology. 147(3)
- Publication Year :
- 2020
-
Abstract
- Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients. The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton. In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406–32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219–24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib. Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Adult
Male
Cancer Research
Lung Neoplasms
medicine.drug_class
Tyrosine-kinase inhibitor
03 medical and health sciences
0302 clinical medicine
Crizotinib
Carcinoma, Non-Small-Cell Lung
medicine
Humans
Anaplastic Lymphoma Kinase
KEGG
Lung cancer
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Aged
Retrospective Studies
Polymorphism, Genetic
business.industry
General Medicine
Middle Aged
Proto-Oncogene Proteins c-met
medicine.disease
030104 developmental biology
STAT1 Transcription Factor
Oncology
030220 oncology & carcinogenesis
Toxicity
Cancer research
Female
Chemical and Drug Induced Liver Injury
business
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 14321335
- Volume :
- 147
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of cancer research and clinical oncology
- Accession number :
- edsair.doi.dedup.....38edfc7b2fe5861dfaccb971c6317b0f