title: Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy.
abstract: The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and -3A5. Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy.
authors.affiliation: Department of Pharmacology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. s.angelini@unibo.it
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
authors.forename: Maria Abbondanza
authors.initials: MA
authors.lastname: Pantaleo
authors.forename: Gloria
authors.initials: G
authors.lastname: Ravegnini
authors.forename: Corrado
authors.initials: C
authors.lastname: Zenesini
authors.forename: Giulia
authors.initials: G
authors.lastname: Cavrini
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Elena
authors.initials: E
authors.lastname: Palassini
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.forename: Monica
authors.initials: M
authors.lastname: Di Battista
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cantelli-Forti
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D018450:Disease Progression; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D027701:Organic Cation Transport Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D000068877:Imatinib Mesylate