Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia

Medical Oncology
Raquel AlvesAna B Sarmento-Ribeiro

Abstract

Although Imatinib and other tyrosine kinase inhibitors (TKIs) have excellent results, the appearance of resistance is a problem in chronic myeloid leukaemia (CML). PI3K/AKT/mTOR pathway is activated by BCR-ABL playing a crucial rule in CML. This study aimed to evaluate the therapeutic potential of Everolimus, in CML models sensitive and resistant to Imatinib. We used one CML cell line sensitive to Imatinib (K562) and two resistant (K562-RC and K56-RD). Cell lines were treated with Everolimus alone and in combination with Imatinib. Cell viability was analysed by resazurin assay. Cell death and cell cycle were analysed by flow cytometry. Additionally, we also studied peripheral blood samples obtained from 52 patients under TKI treatment. Everolimus reduced cell line viability in sensitive (IC50 = 20 µM) and resistant models (K562-RC, IC50 = 25 µM; K562-RD, IC50 = 30 µM). This drug induced cell death by apoptosis and cell cycle arrest in G0/G1 phase. Everolimus also reduced cell viability by increasing apoptosis of haematopoietic stem cells (CD34+ cells) with low cytotoxicity to lymphocytes. Everolimus at 25 µM increased apoptotic cells 18.7% in CD34+ cells and only 8% in lymphocytes. The response to Everolimus was influenced by T...Continue Reading

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Citations

Jan 26, 2021·Frontiers in Oncology·Yimei FengXi Zhang

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