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Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations-Possible Therapeutic Efficacy of Cabozantinib.
Ko, Ya-Chen; Hu, Chung-Yi; Liu, Zheng-Hau; Tien, Hwei-Fang; Ou, Da-Liang; Chien, Hsiung-Fei; Lin, Liang-In.
Afiliación
  • Ko YC; Department of Medical Imaging and Radiological Technology, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan. koyc@mail.ypu.edu.tw.
  • Hu CY; Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. jcyhu@ntu.edu.tw.
  • Liu ZH; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. jcyhu@ntu.edu.tw.
  • Tien HF; Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. B99404035@ntu.edu.tw.
  • Ou DL; Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan. hftien@ntu.edu.tw.
  • Chien HF; Department of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. dlou@ntu.edu.tw.
  • Lin LI; Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110, Taiwan. hfchien@h.tmu.edu.tw.
Int J Mol Sci ; 20(5)2019 Mar 11.
Article en En | MEDLINE | ID: mdl-30862120
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Eliminación de Gen / Resistencia a Antineoplásicos / Secuencias Repetidas en Tándem / Citarabina / Tirosina Quinasa 3 Similar a fms / Mutación Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Eliminación de Gen / Resistencia a Antineoplásicos / Secuencias Repetidas en Tándem / Citarabina / Tirosina Quinasa 3 Similar a fms / Mutación Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza