https://scholars.lib.ntu.edu.tw/handle/123456789/506561
標題: | Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations-Possible Therapeutic Efficacy of Cabozantinib | 作者: | Ko, Ya-Chen CHUNG-YI HU Liu, Zheng-Hau HWEI-FANG TIEN DA-LIANG OU Chien, Hsiung-Fei LIANG-IN LIN |
關鍵字: | Cytarabine; FLT3-ITD; acute myeloid leukemia; drug-resistance | 公開日期: | 11-三月-2019 | 出版社: | MDPI | 卷: | 20 | 期: | 5 | 來源出版物: | International journal of molecular sciences | 摘要: | Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/506561 | ISSN: | 1422-0067 | DOI: | 10.3390/ijms20051230 |
顯示於: | 腫瘤醫學研究所 |
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