PS1170 INFLUX/EFFLUX TRANSPORTERS IN CHRONIC MYELOID LEUKEMIA: THE INFLUENCE OF GENETIC VARIANTS ON SUSCEPTIBILITY AND DRUG RESPONSE

Background: The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) is consider a clinical success, however TKI resistance constitute a clinical problem. Drug resistance can be associated with several mechanisms, which could alter drug target and/or impact drug access to target. TKI resistance mechanisms include mutations of the BCR‐ABL gene and changes on influx and efflux transporters, which affect intracellular drug concentrations. Influx (like OCT1, OCTN2) and efflux transporters (as PgP, BCRP) comprise a variety of proteins express on cell and/or organelles membranes responsible for, respectively, the intrusion or extrusion of substrates, as nutrients, metabolic products, xenobiotics and chemotherapy. Since influx and efflux transporters mediate the intake and extrusion of TKIs, genetic variants on these genes could affect their function and modulate treatment response, as well as influence cancer development. Aims: In this work, we explore the impact of genetic variability (as single nucleotide polymorphisms, SNPs) in genes related with drug transport ( ABCB1, ABCG2, SLC22A1 and SLC22A5 ) on CML susceptibility, drug response and BCR‐ABL mutation status. Methods: In 198 CML patients and 404 controls, ten genetic variants in ABCB1, ABCG2, SLC22A1 and SLC22A5 were genotyped by tetra‐primers‐AMRS‐PCR. The role of these SNPs in CML susceptibility and their association with clinical and laboratory characteristics as well as with therapy response was assessed by logistic regression analysis and/or by Fisher's exact test, with p  < 0.05 considered as significant. Results: Results showed that individuals with AA genotype of ABCB1 gene (rs1045642) are at higher risk of developing CML [Odds ratio (OR): 1.92; 95% confidence interval (CI): 1.134–3.281; P = 0.015] while GG genotype is a protective factor [OR: 0.622; 95% CI: 0.438–0.884; P = 0.008]. GG genotype of ABCG2 (rs2231142) was also associated with high risk for CML development, while allele T presents a protective action [OR: 0.589; 95% CI: 0.388–0.892; P = 0.001]. In both SLC22A5 SNPs we observed that recessive alleles (G for rs274558 and C for rs2631365) confers protection, whereas individual with at least one recessive allele present lower risk to CML development. In our population we also observed an association between CML development and haplotypes as well as genotypic profile (GP). When we look for the influence of these SNPs on drug response, we found that GG genotype (rs2231142 ABCG2) is associated with 6x times more risk of TKI resistance [OR: 6.295; 95% CI: 1.445–27.413; P = 0.0014] while allele T is correlated with a good drug response [OR: 0.176; 95% CI: 0.041–0.753; P = 0.006]. We identify multiple GP that were associated with a high risk of resistance in CML, in particularly a complex GP with ten variants that reveal 21.45 higher risk of resistance [95% CI: 1.087–423.3; P = 0.016]. BCR‐ABL mutation is the predominant mechanism of TKI resistance and we found that CG carriers (rs683369 SLC22A1) presented 4.54 higher risk to develop mutations [95% CI: 1.701–12.11; P = 0.003] and one influx GP was correlated with 13.58 times more probability of acquired BCR‐ABL mutations [95% CI: 1.338–137.8; P = 0.0254]. Summary/Conclusion: In conclusion, our results suggest that genetic variants of influx and efflux transporters genes seem to modulate drug response and are correlated with the acquisition of BCR‐ABL mutations in CML patients. Additionally, these genetic polymorphisms might be involved in the susceptibility for CML development. The work was supported by FMUC, CIMAGO (Project 18/12) and FCT (SFRH/BD/51994/2012).