Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy

Sabrina Angelini, Maria Abbondanza Pantaleo, Gloria Ravegnini, Corrado Zenesini, Giulia Cavrini, Margherita Nannini, Elena Fumagalli, Elena Palassini, Maristella Saponara, Monica Di Battista, Paolo G. Casali, Patrizia Hrelia, Giorgio Cantelli-Forti, Guido Biasco

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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 400 mg 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.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalPharmacological Research
Volume68
Issue number1
DOIs
Publication statusPublished - Feb 2013

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Keywords

  • Gastrointestinal stromal tumours
  • Genetic polymorphisms
  • Imatinib
  • Pharmacogenetic

ASJC Scopus subject areas

  • Pharmacology

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