title: Determinants of Gefitinib toxicity in advanced non-small cell lung cancer (NSCLC): a pharmacogenomic study of metabolic enzymes and transporters.
abstract: Skin rash, diarrhea and hepatotoxicity are the most common toxicities of Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study investigated the effects of genetic polymorphisms of drug target, metabolizing enzymes and transporters on Gefitinib toxicities. Thirty single-nucleotide polymorphisms, including EGFR, cytochromes P450 and ATP-binding cassette (ABC), were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform in 59 non-small cell lung cancer patients treated with Gefitinib. Correlation analyses were performed to evaluate their effects on Gefitinib-induced toxicities. ABCB1 rs1128503 TT genotype was a significant high-risk determinant of both skin rash and diarrhea, with 15.78- and 10.78-fold of incident risk increased, respectively. (odds ratio (OR)=15.78, 95% confidence interval (CI) 2.01-124.1, P=0.0087; OR=10.78, 95% CI 1.54-75.40, P=0.0166 vs non-TT genotypes). Patients with ABCB1 rs1128503 TT genotype had greater risk of skin rash and diarrhea. Therefore, polymorphism analyses of ABCB1 might be beneficial to optimize Gefitinib treatment.
authors.affiliation: Clinical Trial Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Xin
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Clinical Trial Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Clinical Trial Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: L
authors.identifier: 0000-0003-3750-6761
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib