Temsirolimus inhibits cell growth in combination with inhibitors of the B-cell receptor pathway

被引:9
作者
Zoellner, Anna-Katharina [1 ,2 ]
Bayerl, Stephan [2 ]
Hutter, Grit [2 ]
Zimmermann, Yvonne [2 ]
Hiddemann, Wolfgang [1 ,2 ]
Dreyling, Martin [1 ,2 ]
机构
[1] Univ Hosp Munich Grosshadern, Dept Internal Med 3, D-81377 Munich, Germany
[2] Helmholtz Zentrum, Clin Cooperat Grp Leukemia, Munich, Germany
关键词
DLBCL; temsirolimus; mTOR; PI3K; MAMMALIAN TARGET; LYMPHOMA; PI3K; CANCER; MTOR; SURVIVAL; CAL-101; PHOSPHORYLATION; ACTIVATION; EXPRESSION;
D O I
10.3109/10428194.2015.1023720
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Lately, mTOR inhibitors have gained clinical relevance in malignant lymphoma. Still, rapamycin derivatives may activate a pro-survival feedback loop through PI3K-Akt. In this current study, temsirolimus effectively reduced cell growth in GCB and ABC diffuse large cell B-cell lymphoma (GCB = 30-66%, ABC = 45-57%). Combination treatment with the PI3K- inhibitor idelalisib additively effected ABC and GCB lymphoma (GCB = 16-38%, ABC = 25-50%). Since Bruton's Tyrosine Kinase (BTK) plays a significant role for the survival of ABC lymphoma, this study also combined the BTK inhibitor ibrutinib with temsirolimus, which resulted in additive cell growth reduction (ibrutinib 50%, temsirolimus 44%, combination 25%) in ABC lymphoma. In contrast, bortezomib, which has been shown previously to be efficient in ABC lymphoma, revealed an antagonistic effect with temsirolimus in some GCB lymphoma (temsirolimus 53%, temsirolimus + bortezomib 63%). Western blot analysis identified the increase of phosphorylated pro-survival kinases Akt and PDK as a possible underlying mechanism of this interaction.
引用
收藏
页码:3393 / 3400
页数:8
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