{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:23:57Z","timestamp":1791260637227,"version":"4.1.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>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 <jats:italic>ABCB1<\/jats:italic> and <jats:italic>ABCG2.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Aim of the study<\/jats:title><jats:p>In this study, we assessed the impact of inherited variants in <jats:italic>ABCB1<\/jats:italic>, <jats:italic>ABCG2<\/jats:italic>, <jats:italic>PXR<\/jats:italic>, and <jats:italic>CAR<\/jats:italic> genes on dasatinib efficacy and toxicity in CML.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Sixty-one tagging SNPs in <jats:italic>ABCB1<\/jats:italic>, <jats:italic>ABCG2<\/jats:italic>, <jats:italic>PXR<\/jats:italic>, and <jats:italic>CAR<\/jats:italic> genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found the associations between SNPs rs7787082 (<jats:italic>ABCB1<\/jats:italic>, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (<jats:italic>ABCG2<\/jats:italic>, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (<jats:italic>ABCG2<\/jats:italic>, 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 <jats:italic>PXR<\/jats:italic>; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in <jats:italic>CAR<\/jats:italic>; 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 <jats:italic>ABCB1<\/jats:italic>. 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 <jats:italic>ABCB1<\/jats:italic>, 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 <jats:italic>CAR<\/jats:italic>, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in <jats:italic>PXR<\/jats:italic>. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the <jats:italic>ABCB1<\/jats:italic> 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 <jats:italic>ABCG2<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.952640","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T06:24:15Z","timestamp":1663914255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Impact of genetic polymorphisms of drug transporters ABCB1 and ABCG2 and regulators of xenobiotic transport and metabolism PXR and CAR on clinical efficacy of dasatinib in chronic myeloid leukemia"],"prefix":"10.3389","volume":"12","author":[{"given":"Anna 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