Alterations in pharmacogenetic genes and their implications for imatinib resistance in Chronic Myeloid Leukemia patients from an admixed population

• Published in: Cancer chemotherapy and pharmacology 2024-09, Vol.94 (3), p.387-395
• Main Authors: Cereja-Pantoja, Karla Beatriz Cardias, de Brito Azevedo, Tereza Cristina, Vinagre, Lui Wallacy Morikawa Souza, de Moraes, Francisco Cezar Aquino, da Costa Nunes, Giovanna Gilioli, Monte, Natasha, de Alcântara, Angélica Leite, Cohen-Paes, Amanda, Fernandes, Marianne Rodrigues, Batista dos Santos, Sidney Emanuel, de Assumpção, Paulo Pimentel, Ribeiro dos Santos, Ândrea Kely, Burbano, Rommel Mario Rodríguez, Guerrero, Raquel Cruz, Carracedo, Ángel, Carneiro dos Santos, Ney Pereira
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - therapeutic use; Biomarkers; Cancer Research; Chronic myeloid leukemia; Drug metabolism; Drug resistance; Drug Resistance, Neoplasm - genetics; Female; Genes; Genetic diversity; Genotype; Genotypes; Humans; Imatinib; Imatinib Mesylate - therapeutic use; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; Medicine; Medicine & Public Health; Metabolism; Middle Aged; Myeloid leukemia; Oncology; Original Article; Pharmacogenetics; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Population genetics; Population studies; Precision medicine; Protein Kinase Inhibitors - therapeutic use; Quality of life; Treatment resistance; Young Adult
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-024-04689-x

Imatinib is the tyrosine kinase inhibitor used as the gold standard for the treatment of Chronic Myeloid Leukemia. However, about 30% of patients do not respond well to this therapy. Variants in drug administration, distribution, metabolism and excretion (ADME) genes play an important role in drug resistance especially in admixed populations. We investigated 129 patients diagnosed with Chronic Myeloid Leukemia treated with imatinib as first choice therapy. The participants of the study are highly admixed, populations that exhibit genetic diversity and complexity due to the contributions of multiple ancestral groups. Thus, the aim of this work was to investigate the association of 30 SNVs in genes related to response to treatment with Imatinibe in CML. Our results indicated that for the rs2290573 of the ULK3 gene, patients with the recessive AA genotype are three times more likely to develop resistance over time (secondary resistance) ( p  = 0.019, OR = 3.19, IC 95%= 1.21–8.36). Finally, we performed interaction analysis between the investigated variants and found several associations between SNVs and secondary resistance. We concluded that the variant rs2290573 of the ULK3 gene may be relevant for predicting treatment response of CML with imatinib, as well as possible treatment resistance. The use of predictive biomarkers is an important tool for therapeutic choice of patients, improving their quality of life and treatment efficacy.