Impact of genetic polymorphisms of drug transporters and and regulators of xenobiotic transport and metabolism and on clinical efficacy of dasatinib in chronic myeloid leukemia.

Introduction: Functional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of and

Aim Of The Study: In this study, we assessed the impact of inherited variants in , , , and genes on dasatinib efficacy and toxicity in CML.

Materials And Methods: Sixty-one tagging SNPs in , , , and genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy.

Results: We found the associations between SNPs rs7787082 (, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in ; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in ; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in . Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in , rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in , and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in . Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model.

Conclusion: Our data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients.