Genetic Association of Drug Response to Erlotinib in Chinese Advanced Non-small Cell Lung Cancer Patients

Abstract

The efficacy of erlotinib treatment for advanced non-small cell lung cancer (NSCLC) is due to its action as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Patients treated with erlotinib experience different drug responses. The effect of germline mutations on therapeutic responses and adverse drug responses (ADRs) to erlotinib in Chinese patients requires elucidation. Sixty Han Chinese advanced non-small cell lung cancer patients received erlotinib monotherapy and, for each participant, 76 candidate genes (related to EGFR signaling, drug metabolism and drug transport pathways) were sequenced and analyzed. The single-nucleotide polymorphisms (SNPs) rs1042640 in UGT1A10, rs1060463, and rs1064796 in CYP4F11, and rs2074900 in CYP4F2 were significantly associated with therapeutic responses to erlotinib. Rs1064796 in CYP4F11 and rs10045685 in UGT3A1 were significantly associated with adverse drug reaction. Moreover, analysis of a validation cohort confirmed the significant association between rs10045685 in UGT3A1 and erlotinib adverse drug response(unadjusted p = 0.015). This study provides comprehensive, systematic analyses of genetic variants associated with responses to erlotinib in Chinese advanced non-small cell lung cancer patients. Newly-identified SNPs may serve as promising markers to predict responses and safety in erlotinib-treated advanced non-small cell lung cancer patients after chemotherapy doublet.

The correlation between CYP4F2 variants and chronic obstructive pulmonary disease risk in Hainan Han population

“…In the year of 2011, the expression of CYP4F2 was found by Falus et al to be a rapid elevation when children with respiratory disease to polarized light therapy [29]. In 2018, rs2074900 in CYP4F2 was found to be significantly related to therapeutic responses to erlotinib in sixty Han Chinese advanced non-small cell lung cancer patients received erlotinib monotherapy [16]. The above results indicated that CYP4F2 was involved in the pathogenesis of pulmonary disease and CYP4F2 variants played a vital role in the lung disease.…”

“…And Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) encodes a member of the cytochrome P450 superfamily of enzymes involved in many metabolic pathways [14,15]. It is responsible for metabolizing arachidonic acid to 20-hydroxyeicosatetraenoic acid and involved in many reactions, such as drug metabolism [16], long-chain fatty acids metabolism [17], and synthesis of cholesterol, steroids and other lipids. Recently, Wang et al elucidated that the upregulated differentially expressed genes were significantly enriched in the arachidonic acid metabolism pathway, including CYP4F2, PTGDS and PLA2G16 by pathway enrichment analysis and pathway interactive network construction [18].…”

Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment

“…The main focus has been on the variability in the emergence of skin rash. These studies have been conducted mainly using targeted approaches, either focusing on the erlotinib target (EGFR) or on erlotinib metabolizing and transporting enzymes, by studying single nucleotide polymorphisms (SNPs) in genes as well as sequencing of entire genes [58,60,65,[80][81][82][83][84][85][86][87][88].…”

“…The ABCB1 haplotype 1236TT-2677TT-3435TT has been associated with skin rash and with erlotinib plasma concentration [87]. Several metabolizing enzymes have been studied, for instance, have SNPs in CYP27B1 (rs8176345), CYP4F11 (rs1064796) and UGT3A1 (rs10045685) have been associated with skin rash and adverse drug reactions in erlotinib treated patients [81,83].…”

The Roles of Common Variation and Somatic Mutation in Cancer Pharmacogenomics

“…Wang and colleagues performed targeted sequencing to evaluate the link between EGFR and EGFR -linked pathway gene SNPs with EGFR -TKI response and ADRs in patients with advanced NSCLC [ 55 ]. They identified rs1042640 in UGT1A10 , rs1060463 and rs1064796 in CYP4F11 and rs2074900 in CYP4F2 as being associated with erlotinib treatment response, with improved an median PFS of 12.57 months compared to that of non-responders (median PFS 3.55 months) [ 55 ]. SNP rs1064796 in CYP4F11 and SNP rs10045685 in UGT3A1 were also linked to ADRs, with carriers of CYP4F11 -rs1064796-C and UGT3A1 -G showing an increased risk for skin rash or digestive track injury [ 55 ].…”