Association Between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients

Overview

Journal J Clin Med

Specialty General Medicine

Date 2022 Oct 27

PMID 36294538

Authors

Natalia Estrada

Lurdes Zamora

Francisca Ferrer-Marin

Laura Palomo

Olga Garcia

Patricia Velez

Iris De la Fuente

Miguel Sagues

Marta Cabezon

Montserrat Cortes

Rolando Omar Vallansot

Maria Alicia Senin-Magan

Concepcion Boque

Blanca Xicoy

Affiliations

Soon will be listed here.

Abstract

Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (-rs492338, -rs496550, -rs497692, -rs1135840, -rs7003319, -rs4934027 and -rs628031) and one haplotype in the gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.

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References

Branford S, Hughes T, Rudzki Z . Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol. 1999; 107(3):587-99. DOI: 10.1046/j.1365-2141.1999.01749.x. View

Hochhaus A, Baccarani M, Silver R, Schiffer C, Apperley J, Cervantes F . European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34(4):966-984. PMC: 7214240. DOI: 10.1038/s41375-020-0776-2. View

Arbitrio M, Di Martino M, Scionti F, Agapito G, Guzzi P, Cannataro M . DMET™ (Drug Metabolism Enzymes and Transporters): a pharmacogenomic platform for precision medicine. Oncotarget. 2016; 7(33):54028-54050. PMC: 5288240. DOI: 10.18632/oncotarget.9927. View

Polillo M, Galimberti S, Barate C, Petrini M, Danesi R, Di Paolo A . Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia. Int J Mol Sci. 2015; 16(9):22811-29. PMC: 4613337. DOI: 10.3390/ijms160922811. View

Kim D, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K . Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009; 15(14):4750-8. DOI: 10.1158/1078-0432.CCR-09-0145. View

Cargnin S, Ravegnini G, Soverini S, Angelini S, Terrazzino S . Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis. Pharmacol Res. 2018; 131:244-254. DOI: 10.1016/j.phrs.2018.02.005. View

Maffioli M, Camos M, Gaya A, Hernandez-Boluda J, Alvarez-Larran A, Domingo A . Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia. Leuk Res. 2010; 35(8):1014-9. DOI: 10.1016/j.leukres.2010.12.004. View

Lima L, Bueno C, Vivona D, Hirata R, Hirata M, Hungria V . Relationship between SLCO1B3 and ABCA3 polymorphisms and imatinib response in chronic myeloid leukemia patients. Hematology. 2014; 20(3):137-42. DOI: 10.1179/1607845414Y.0000000181. View

Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J . Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008; 112(5):2024-7. DOI: 10.1182/blood-2008-03-147744. View

10.

Mahon F . Treatment-free remission in CML: who, how, and why?. Hematology Am Soc Hematol Educ Program. 2017; 2017(1):102-109. PMC: 6142562. DOI: 10.1182/asheducation-2017.1.102. View

11.

Thomas J, Wang L, Clark R, Pirmohamed M . Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004; 104(12):3739-45. DOI: 10.1182/blood-2003-12-4276. View

12.

Ravegnini G, Urbini M, Simeon V, Genovese C, Astolfi A, Nannini M . An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor. Pharmacogenomics J. 2018; 19(4):390-400. DOI: 10.1038/s41397-018-0050-4. View

13.

Nieuweboer A, Smid M, de Graan A, Elbouazzaoui S, de Bruijn P, Martens J . Predicting paclitaxel-induced neutropenia using the DMET platform. Pharmacogenomics. 2015; 16(11):1231-41. DOI: 10.2217/pgs.15.68. View

14.

Ni L, Li J, Miao K, Qiao C, Zhang S, Qiu H . Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2010; 28(1):265-9. DOI: 10.1007/s12032-010-9456-9. View

15.

Arbitrio M, Di Martino M, Barbieri V, Agapito G, Guzzi P, Botta C . Identification of polymorphic variants associated with erlotinib-related skin toxicity in advanced non-small cell lung cancer patients by DMET microarray analysis. Cancer Chemother Pharmacol. 2015; 77(1):205-9. DOI: 10.1007/s00280-015-2916-3. View

16.

Ben Hassine I, Gharbi H, Soltani I, Ben Hadj Othman H, Farrah A, Amouri H . Molecular study of ABCB1 gene and its correlation with imatinib response in chronic myeloid leukemia. Cancer Chemother Pharmacol. 2017; 80(4):829-839. DOI: 10.1007/s00280-017-3424-4. View

17.

Kennedy M, Barrera G, Nakamura K, Baldan A, Tarr P, Fishbein M . ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 2005; 1(2):121-31. DOI: 10.1016/j.cmet.2005.01.002. View

18.

Soverini S, Branford S, Nicolini F, Talpaz M, Deininger M, Martinelli G . Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2013; 38(1):10-20. DOI: 10.1016/j.leukres.2013.09.011. View

19.

Tarling E, Edwards P . ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter. Proc Natl Acad Sci U S A. 2011; 108(49):19719-24. PMC: 3241749. DOI: 10.1073/pnas.1113021108. View

20.

Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M . Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2012; 98(2):193-200. PMC: 3561425. DOI: 10.3324/haematol.2012.066480. View