Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells.
Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells.
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DOI：
10.1038/s41375-018-0032-1
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发表时间：
2018-08
期刊：
影响因子：
11.4
通讯作者：
Cutillas PR
中科院分区：
文献类型：
--
作者：
Casado P;Wilkes EH;Miraki-Moud F;Hadi MM;Rio-Machin A;Rajeeve V;Pike R;Iqbal S;Marfa S;Lea N;Best S;Gribben J;Fitzgibbon J;Cutillas PR
激酶抑制剂在恶性细胞表现出对靶向激酶[1]的依赖或成瘾的情况下有效降低癌细胞活力。基因改变可导致促生存和增殖途径的组成性激活，并常常决定癌细胞对靶向药物的反应程度[2,3]。然而，与基因突变没有直接联系的其他生化事件也可能有助于致癌激酶活性的调节，从而影响对激酶靶向药物的反应[4,5]。在这里，我们整合了原发AML的药物敏感性、蛋白质组学、磷酸化蛋白质组学、免疫表型和基因组分析，以使反应合理化，并确定AML细胞对该疾病临床和临床前感兴趣的靶向化合物敏感性的决定因素。我们研究了FLT3/PKC （midosvin）、PAK （PF-3758309）、CK2 （silmitasertib）、MEK （trametinib）和P38 （TAK-715）激酶抑制剂对细胞活力的影响。以下分别命名为FLT3/PKCi， PAKi, CK2i，
Kinase inhibitors are efficient in reducing cancer cell viability in cases where malignant cells present a dependency or addiction to the targeted kinase [1]. Genetic alterations can cause constitutive activation of pro-survival and proliferative pathways and often determine the extent by which cancer cells respond to targeted drugs [2, 3]. However, other biochemical events, not directly linked to genetic mutations may also contribute to the modulation of oncogenic kinase activity and thus influence responses to kinase targeted drugs [4, 5]. Here, we integrated drug sensitivity, proteomic, phosphoproteomic, immunophenotypic, and genomic analyses of primary AML to rationalize responses and identify determinants of sensitivity of AML cells to targeted compounds of clinical and preclinical interest in this disease. We investigated the effects on cell viability of inhibitors for the kinases FLT3/PKC (midostaurin), PAK (PF-3758309), CK2 (silmitasertib), MEK (trametinib), and P38 (TAK-715). Hereafter named as FLT3/PKCi, PAKi, CK2i,
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影响因子：
2.9
作者：
Wang, Yanfeng;Yin, Ophelia Q. R.;Schran, Horst
通讯作者：
Schran, Horst
影响因子：
4
作者：
Workman, Paul;Al-Lazikani, Bissan;Clarke, Paul A.
通讯作者：
Clarke, Paul A.
影响因子：
64.8
作者：
Straussman, Ravid;Morikawa, Teppei;Shee, Kevin;Barzily-Rokni, Michal;Qian, Zhi Rong;Du, Jinyan;Davis, Ashli;Mongare, Margaret M.;Gould, Joshua;Frederick, Dennie T.;Cooper, Zachary A.;Chapman, Paul B.;Solit, David B.;Ribas, Antoni;Lo, Roger S.;Flaherty, Keith T.;Ogino, Shuji;Wargo, Jennifer A.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
28.2
作者：
Pemovska, Tea;Kontro, Mika;Wennerberg, Krister
通讯作者：
Wennerberg, Krister
影响因子：
3.4
作者：
Leonowens, Cathrine;Pendry, Carolyn;Ouellet, Daniele
通讯作者：
Ouellet, Daniele