ABCMdb

PMID: 20532504

Buda G, Ricci D, Huang CC, Favis R, Cohen N, Zhuang SH, Harousseau JL, Sonneveld P, Blade J, Orlowski RZ
Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin.
Ann Hematol. 2010 Nov;89(11):1133-40. Epub 2010 Jun 8., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC1 p.Arg723Gln The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD+ bortezomib. Login to comment 30 ABCC1 p.Arg723Gln Like MDR1, it confers resistance to anthracyclines [19], and because the MRP1 mutation Arg723Gln has an effect on MRP1 expression and trafficking, it significantly reduced MRP1-mediated resistance to a wide spectrum of drugs [20]. Login to comment 33 ABCC1 p.Arg723Gln Specifically, we tested for the presence of the MDR1 polymorphisms 1236C>T, 2677G>W (W=T or A), and 3435C>T and the MRP1 gene R723Q polymorphism. Login to comment 43 ABCC1 p.Arg723Gln Analyses The objectives of the pharmacogenomic analyses were to test whether the MDR1 gene polymorphisms-3435C>T (RefSNP ID rs1045642), 2677G>W (W=T or A; RefSNP ID rs2032582), and 1236C>T (RefSNP ID rs1128503), and the MRP1 gene R723Q polymorphism (RefSNP ID rs4148356), were associated with a different overall response rate (CR+partial response) and response durability (TTP, PFS, and OS). Login to comment 67 ABCC1 p.Arg723Gln Influence of MDR1 and MRP1 SNPs The possible presence of associations between 1236C>T, 2677G>W (W=Tor A), and 3435C>T in MDR1 and R723Q in MRP1 and the response rate of the bortezomib or PLD+ bortezomib groups, as well as response durability measures, were then evaluated. Login to comment 70 ABCC1 p.Arg723Gln In the present study, the MRP1 gene polymorphism R723Q was significantly associated with time to progression (Fig. 1a; p= 0.0008), progression-free survival (Fig. 1b; p=0.0006), and overall survival (Fig. 1c; p=0.0045) in subjects who received PLD+bortezomib. Login to comment 76 ABCC1 p.Arg723Gln Table 2 Summary statistics of the studied genetic markers Marker Frequency minor allele Hardy-Weinberg equilibrium p value n/Genotype frequencies of homozygous wild type n/Genotype frequencies of heterozygous n/Genotype frequencies of homozygous variant Missing data MDR1 1236C>T 0.4355 0.6110 91 (0.3262) 133 (0.4767) 55 (0.1971) 0 MDR1 2677G>W 0.4373 0.7430 87 (0.3118) 140 (0.5018) 52 (0.1864) 0 MDR1 3435C>T 0.4910 0.8145 73 (0.2626) 137 (0.4928) 68 (0.2446) 1 MRP1 R723Q 0.0090 0.8800 274 (0.9821) 5 (0.0179) 0 (0) 0 Patient Prior therapies Paraprotein type and level Cytogenetics 1 1. Login to comment 81 ABCC1 p.Arg723Gln ABCC1 p.Arg723Gln Doxorubicin, melphalan, cyclophosphamide Table 3 Clinical characteristics of patients with the MRP1 R723Q polymorphism a b c Fig. 1 Time to progression (panel a), progression-free survival (panel b), and overall survival (panel c) of patients treated for their relapsed and/or refractory multiple myeloma with PLD+bortezomib is plotted based on the presence of either the A/G or G/G SNP at R723Q in MRP 1 using the Kaplan-Meier method Discussion The introduction of novel agents, and their use in rationally designed combination regimens, has revolutionized the therapy of multiple myeloma and contributed to an increasing overall survival [23, 24]. Login to comment 87 ABCC1 p.Arg723Gln Fig. 2 Progression-free survival of patients treated for their relapsed and/or refractory multiple myeloma with PLD+bortezomib is plotted based on the presence of either the C/C, C/T, or T/T SNP at C3435T in MDR1 using the Kaplan-Meier method Fig. 3 Time to progression of patients treated for their relapsed and/or refractory multiple myeloma with PLD+bortezomib is plotted based on the presence of the five most common MDR1 diplotypes using the Kaplan-Meier method In the present retrospective study, the MRP1 gene polymorphism R723Q was significantly associated with TTP (Fig. 1a), PFS (Fig. 1b), and OS (Fig. 1c) in subjects who received PLD+bortezomib. Login to comment 88 ABCC1 p.Arg723Gln Studies of the MRP1 mutation Arg723Gln have not shown that it impacts on model substrate transport [30], but it does reduce resistance to agents such as daunorubicin and doxorubicin [19], and thus it may exert its effect instead through MRP1 expression and trafficking. Login to comment 90 ABCC1 p.Arg723Gln Since anthracyclines exert their antitumor effects in part through the induction of just such stress [33], it may be differences in the ability of the MRP1 R723Q isoform to play such a role that increased the sensitivity to PLD+bortezomib, though this hypothesis will require laboratory testing. Login to comment 91 ABCC1 p.Arg723Gln Moreover, further studies of the impact of the MRP1 R723Q allele will be needed to confirm our findings, given the few subjects with this genotype that were present in our population. Login to comment