Targeting UPR signaling pathway by dasatinib as a promising therapeutic approach in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disease that mediated by BCR / ABL oncogenic signaling. CML can be targeted with the imatinib, dasatinib, and nilotinib TKI inhibitors, the latter two of them have been approved for imatinib-resistant or -intolerant CML patients. The TKIs resist...

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Published in:Medical oncology (Northwood, London, England) London, England), 2022-09, Vol.39 (9), p.126-126, Article 126
Main Authors: Ozel, Buket, Kipcak, Sezgi, Biray Avci, Cigir, Sabour Takanlou, Maryam, Sabour Takanlou, Leila, Tezcanli Kaymaz, Burcin, Karatekin, Ilknur, Gunduz, Cumhur, Selvi Gunel, Nur
Format: Article
Language:English
Subjects:
Binding sites
Breast cancer
Cytotoxicity
Hematology
Internal Medicine
Kinases
Leukemia
Medicine
Medicine & Public Health
Mutation
Oncology
Original Paper
Pathology
Protein folding
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Summary:Chronic myeloid leukemia (CML) is a myeloproliferative disease that mediated by BCR / ABL oncogenic signaling. CML can be targeted with the imatinib, dasatinib, and nilotinib TKI inhibitors, the latter two of them have been approved for imatinib-resistant or -intolerant CML patients. The TKIs resistance occurs by different molecular mechanisms, including overexpression of BCR-ABL , mutations in the TKI binding site of BCR / ABL , and ER-stress. Unfolded protein responses (UPR) is a cytoprotective mechanism which is activated by ER-stress. The IRE1 , PERK , and ATF6 are three main arms of the UPR mechanism and are activated by a common mechanism involving the dissociation of the ER-chaperone BiP / GP78 . There is a correlation between ER-stress, CML progression, and response to TKI treatment. In the present study, we aimed to determine alterations of the expression levels of genes related to UPR pathway signaling after treatment with dasatinib in K562 chronic myeloid leukemia cell line by quantitative RT-PCR relatively. The array-data revealed that treatment with dasatinib significantly decreased the UPR mechanism-related genes (including HSPA1B , HSPA2 , HSPA4L , ATF6 , ATF6B , CEBPB, PERK, TRIB3 , DNAJB , ERN1, and UHRF1 ) in K562 cells. In conclusion, the results showed that dasatinib regulates the UPR mechanism that plays a significant role in cancer progression and therapy resistance in CML. Thus, dasatinib-induced dysfunction of the UPR mechanism may promise encouraging therapy for CML. Graphical abstract
ISSN:1559-131X
1357-0560
1559-131X
DOI:10.1007/s12032-022-01714-y