Association of JAK/STAT pathway gene polymorphisms with EGFR-TKIs adverse drug reactions in patients with advanced NSCLC

Abstract Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been confirmed as an effective therapy for advanced non-small cell lung cancer (NSCLC) patients with EGFR-positive. However, various adverse drug reactions (ADRs) are frequently occurred in patients treated with EGFR-TKIs. Genetic polymorphisms may predict EGFR-TKI-induced ADRs. We attempted to explored the potential association between the genetic polymorphisms of the JAK-STAT pathway and EGFR-TKIs related ADRs in non-small cell lung cancer (NSCLC) patients. In addition, we also researched the correlation between single nucleotide polymorphisms (SNPs) of Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) pathway and clinical survival outcomes of NSCLC patients treated with EGFR-TKIs.Methods: We recruited 162 Han Chinese patients with advanced non-small cell lung cancer. We analyzed the relationship between the adverse reactions of EGFR-TKIs and JAK-STAT signaling pathway by single factor and multi-factor logistic regression analysis. Kaplan–Meier test was used to evaluate the association of SNPs with progression-free survival of advanced NSCLC patients.Results: In the discovery group, we found the following: There were significantly associations between the severity of adverse drug reactions caused by EGFR-TKIs and rs1053023 (P=0.016), rs1053005 (P = 0.016) in STAT3, rs324011 (P= 0.019) in STAT6. Furthermore, patients with AA genotype had a prolonged progression-free survival (PFS) (P= 0.012) compared with AT and TT genotype of rs7043371. Besides, validation experiments showed that STAT3 rs1053023 (P=0.021), rs1053005 (P = 0.021), STAT6 rs324011 (P=0.002) were all significantly associated with the severity of ADRs induced by EGFR-TKIs by multivariable regression, which consistent with the study in the discovery group.Conclusions: STAT3 rs1053023, rs1053005 and STAT6 rs324011 might be potential predictors of the severity of ADRs in EGFR-TKIs treated NSCLC patients and their variants play important roles in predicting the adverse reactions of non-small cell lung cancer patients with EGFR-TKIs.