Resistance to targeted therapy in CML patientsaccording to next generation sequencing (NGS)

Background: Chronic myeloid leukemia (CML) is a group ofmyeloproliferative neoplasms characterized by the uncontrolledgrowth of myeloid cells at various stages of development. Thederegulated BCR-ABL۱ tyrosine kinase due to the fusion generesulting from the Philadelphia translocation (t (۹;۲۲) (q۳۴;q۱۱)) can be therapeutically targeted. Recent studies have identifiedmutations in the BCR-ABL۱ gene in patients, resulting inresistance to Tyrosine Kinase Inhibitors (TKIs), the most commontreatment for CML. Next-generation sequencing (NGS)has been widely used to identify mutations and subtypes of diseasesin recent years. Sequencing of gene panels, transcriptomesequencing, exome sequencing, and whole genome sequencing(WGS) are all examples of NGS.Materials and Methods: The data for this cross-sectionalstudy were gathered from the COSMIC database. In this study,۱۵۴ CML patients with mutations in the BCR-ABL۱ gene wereidentified by NGS, and drug resistance to TKIs and imatinibwas evaluated. The statistical analysis was performed using theR programming language.Results: There were significant drug resistance findings inCML patients with positive BCR-ABL۱ regarding the first generationof tyrosine kinase inhibitors, especially imatinib andother TKIs with mutations in the translocation ۹:۲۲ (Philadelphia)and of NS origin. It was observed that NS subjects weresignificantly more resistant to imatinib drugs when comparedto Ph subjects.Discussion: ABL۱ represents a variety of functions, includinginhibiting cell cycle progression and proliferation, signalingthrough integrins, and repairing DNA. It is typical for the ABL۱kinase to be inactive and must be activated to function. A BCR/ABL۱ fusion produces an oncoprotein that results in increasedproliferation, abnormal adhesion, reduced apoptosis, migration,and malignancy, as well as clonal expansion of hematopoieticcells. There are three generations of TKIs, which disrupt the signaltransduction pathways of protein kinases in multiple ways.Imatinib as the TKI-resistant drug binds to the ATP binding site of the target kinase and prevents the transfer of phosphate fromATP to the tyrosine residues of the ABL۱ protein

کلیدواژه ها:

Targeted therapy ، Next generation sequencing (NGS) ، Chronic myeloid leukemia (CML) ، TKIs ، BCR_ABL۱