Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Rajamani, Bharathi M; Benjamin, Esther Sathya Bama; Abraham, Aby; Ganesan, Sukanya; Lakshmi, Kavitha M; Anandan, Sambandam; Karathedath, Sreeja; Varatharajan, Savitha; Mohanan, Ezhilpavai; Janet, Nancy Beryl; Srivastava, Vivi M.; Velayudhan, Shaji R; Kulkarni, Uday; Devasia, Anup J.; Na, Fouzia; Korula, Anu; George, Biju; Srivastava, Alok; Balasubramanian, Poonkuzhali

doi:10.1038/s41598-020-77140-9

Cited by 8 publications

(11 citation statements)

References 65 publications

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“…ABCB1 is one of the most well-established ABC transporters that mediates MDR in cancer cells. To dates, a wide range of anticancer drugs were iden-tified as substrates of ABCB1, including chemotherapeutic agents doxorubicin, paclitaxel, vincristine 57 , and tyrosine kinase inhibitors GSK1070916 58 , WYE354 59 , imatinib 60 . suggesting the anticancer effect may be attenuated in ABCB1-overexpressing cancer cells.…”

Section: Abcb Subfamilymentioning

confidence: 99%

ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates

Wang

Yang

et al. 2021

J Evidence Based Medicine

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The ATP-binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross-membrane transportation of various endo-and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure-function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies. INTRODUCTIONSince the first discovery of the membrane transport protein Pglycoprotein (P-gp) or ATP-binding cassette (ABC) transporter B1 (ABCB1) in resistant cancer cells in the mid-1970s, more and more members in ABC transporter superfamily such as ABCG2 (breast cancer resistance protein, BCRP) and MRPs (multidrug resistance proteins) were discovered and characterized, especially the structurefunction relationship and their roles in tumorigenesis 1 (Figure 1). ABC transporter proteins are best known for mediating multidrug resistance (MDR) in cancer and lead to failure of chemotherapy. Besides, studies also revealed their critical roles in cancer as more than efflux pumps. 2,3 ABC transporter superfamily is composed of 7 subfamilies, namely ABCA to ABCG In human the ABC transporter superfamily is divided into least 48 members with different functions.

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Section: Abcb Subfamilymentioning

confidence: 99%

ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates

Wang

Yang

et al. 2021

J Evidence Based Medicine

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“…After screening the titles and abstracts of articles, 47 studies were excluded because they were deemed repetitive or unqualified. After reading 28 potentially eligible papers, six studies from the literature met our inclusion criteria [ 14 , 15 , 16 , 17 , 18 , 19 ]. The study by Rajamani et al did not report imatinib plasma C trough for individual genotypes, but the authors provided the data on our request [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…After reading 28 potentially eligible papers, six studies from the literature met our inclusion criteria [ 14 , 15 , 16 , 17 , 18 , 19 ]. The study by Rajamani et al did not report imatinib plasma C trough for individual genotypes, but the authors provided the data on our request [ 14 ]. No additional studies were obtained by checking the reference lists of these articles.…”

Section: Resultsmentioning

confidence: 99%

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Fratte

Polesel

Gagno

et al. 2023

IJMS

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Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.

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“…TKI efficacy is highly dependent on cellular drug concentration to effectively block BCR-ABL activity, and low TKI concentrations have already been associated, at least in part, with reduced expression or activity of SLC transporters and/or increased expression or activity of ABC transporters [ 40 , 41 ]. The SNVs studied here, which are associated with altered expression and activity, have a potential role in response to therapy [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…The SNVs studied here, which are associated with altered expression and activity, have a potential role in response to therapy [ 42 , 43 ]. Recently Rajamani et al showed the influences of ABCB1 polymorphisms and plasma imatinib levels on early molecular response and failure-free survival [ 41 ]. Despite frequently having been associated with response by other authors [ 5 , 8 , 44 , 45 ], P-gP SNVs did not present a prognostic impact in our study.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis

Alves

Gonçalves

Jorge

et al. 2022

IJMS

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Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection.

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Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Cited by 8 publications

References 65 publications

ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates

ATP‐binding cassette (ABC) transporters in cancer: A review of recent updates

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis

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