Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients
Shuang Xin1,2, Wenfeng Fang2, Jianwen Li3
1Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510060, People's Republic of China.
Purpose:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
A specific gene polymorphism, STAT1 rs10208033, can predict crizotinib-induced liver toxicity in ALK-positive non-small cell lung cancer patients. This finding highlights STAT1
Area of Science:
- Pharmacogenomics
- Oncology
- Hepatotoxicity
Background:
- Crizotinib is a key targeted therapy for ALK-positive non-small cell lung cancer (NSCLC).
- Hepatotoxicity is a significant side effect of crizotinib treatment.
- Understanding genetic factors influencing crizotinib-induced liver injury is crucial for personalized medicine.
Purpose of the Study:
- To investigate the association between genetic variations in RTK downstream signaling pathways and crizotinib-induced hepatotoxicity.
- To identify potential genetic biomarkers for predicting liver toxicity in ALK-positive NSCLC patients treated with crizotinib.
Main Methods:
- Retrospective pharmacogenomic analysis of 42 ALK-positive NSCLC patients treated with crizotinib.
- Variable importance analysis using random forest to identify significant genetic features.
- Genotyping of 90 polymorphisms and sequencing of HGFR (c-Met) genes.
- Pathway enrichment analysis (KEGG, Reactome) and differential gene expression analysis.
Main Results:
- 66.7% of NSCLC patients experienced crizotinib-induced liver toxicity, with 11.9% developing severe cases.
- STAT1 rs10208033 (T>C) polymorphism was significantly associated with increased risk of crizotinib-induced liver toxicity (OR=6.733, P=0.017).
- STAT1 inhibitor showed potential to protect hepatocytes from crizotinib toxicity in vitro.
Conclusions:
- The STAT1 rs10208033 polymorphism is a potential predictive biomarker for crizotinib-induced hepatotoxicity.
- STAT1 plays a critical role in the development of crizotinib-induced liver injury.
- Further research is warranted to validate these findings and elucidate the underlying mechanisms.
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