Mariamena Arbitrio1, Maria Teresa Di Martino2, Vito Barbieri3, Giuseppe Agapito4, Pietro Hiram Guzzi4, Cirino Botta2, Eleonora Iuliano2, Francesca Scionti5, Emanuela Altomare2, Stefania Codispoti2, Serafino Conforti6, Mario Cannataro4,7, Pierfrancesco Tassone2,3,8, Pierosandro Tagliaferri9,10. 1. ISN-CNR, Roccelletta di Borgia, Catanzaro, Italy. 2. Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy. 3. Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, Catanzaro, Italy. 4. Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy. 5. Department of Pediatrics, Magna Graecia University, Catanzaro, Italy. 6. Medical Oncology Unit, Mariano Santo Hospital, Cosenza, Italy. 7. ICAR-CNR, Cosenza, Italy. 8. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. 9. Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy. pierosandrotagliaferri@gmail.com. 10. Medical Oncology Unit, Mater Domini Hospital, Salvatore Venuta University Campus, Catanzaro, Italy. pierosandrotagliaferri@gmail.com.
Abstract
PURPOSE: Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. METHODS: In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). RESULTS: Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. CONCLUSION: Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.
PURPOSE:Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancerpatients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. METHODS: In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). RESULTS: Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. CONCLUSION: Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.
Authors: Kevin M Huang; Muhammad Erfan Uddin; Duncan DiGiacomo; Maryam B Lustberg; Shuiying Hu; Alex Sparreboom Journal: Expert Opin Drug Metab Toxicol Date: 2020-04-26 Impact factor: 4.481
Authors: Mariamena Arbitrio; Maria Teresa Di Martino; Francesca Scionti; Giuseppe Agapito; Pietro Hiram Guzzi; Mario Cannataro; Pierfrancesco Tassone; Pierosandro Tagliaferri Journal: Oncotarget Date: 2016-08-16
Authors: Katia Grillone; Caterina Riillo; Francesca Scionti; Roberta Rocca; Giuseppe Tradigo; Pietro Hiram Guzzi; Stefano Alcaro; Maria Teresa Di Martino; Pierosandro Tagliaferri; Pierfrancesco Tassone Journal: J Exp Clin Cancer Res Date: 2020-06-20
Authors: Tristan M Sissung; Arun Rajan; Gideon M Blumenthal; David J Liewehr; Seth M Steinberg; Arlene Berman; Giuseppe Giaccone; William D Figg Journal: PLoS One Date: 2019-02-28 Impact factor: 3.240