P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.
P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.
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P2RY2-AKT激活是急性髓性白血病XPO1抑制的治疗可操作的结果。
DOI：
10.1038/s43018-022-00394-x
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发表时间：
2022-07
期刊：
影响因子：
22.7
通讯作者：
Wood, Kris C.
中科院分区：
文献类型：
--
作者：
Lin, Kevin H.;Rutter, Justine C.;Xie, Abigail;Killarney, Shane T.;Vaganay, Camille;Benaksas, Chaima;Ling, Frank;Sodaro, Gaetano;Meslin, Paul-Arthur;Bassil, Christopher F.;Fenouille, Nina;Hoj, Jacob;Washart, Rachel;Ang, Hazel X.;Cerda-Smith, Christian;Chaintreuil, Paul;Jacquel, Arnaud;Auberger, Patrick;Forget, Antoine;Itzykson, Raphael;Lu, Min;Lin, Jiaxing;Pierobon, Mariaelena;Sheng, Zhecheng;Li, Xinghai;Chilkoti, Ashutosh;Owzar, Kouros;Rizzieri, David A.;Pardee, Timothy S.;Benajiba, Lina;Petricoin, Emanuel;Puissant, Alexandre;Wood, Kris C.
Selinexor是核输出蛋白XPO 1的第一种抑制剂，最近FDA批准用于治疗多发性骨髓瘤和弥漫性大B细胞淋巴瘤。在复发性/难治性急性髓性白血病（AML）中，selinexor显示出有希望的活性，表明基于selinexor的联合治疗可能具有临床潜力。在这里，出于以下假设，即赛林克斯的核螯合的不同底物对AML细胞施加多效性健身效果，我们系统地分类赛林克斯治疗的亲和反健身后果。我们发现，selinexor通过上调嘌呤能受体P2 RY 2激活AML中的PI 3 K γ依赖性AKT信号传导。抑制该轴可增强赛林克斯在AML细胞系、患者源性原代培养物和多种AML小鼠模型中的抗白血病作用。在同基因MLL-AF 9驱动的AML小鼠模型中，selinexor和ipatasertib治疗优于标准治疗化疗和selinexor化疗。总之，这些发现确立了药物诱导的P2 RY 2-AKT信号传导是AML中XPO 1抑制的可操作结果。
Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently FDA-approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor’s nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalogue the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures, and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.
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影响因子：
11.4
作者：
Etchin, J.;Sun, Q.;Kentsis, A.;Farmer, A.;Zhang, Z. C.;Sanda, T.;Mansour, M. R.;Barcelo, C.;McCauley, D.;Kauffman, M.;Shacham, S.;Christie, A. L.;Kung, A. L.;Rodig, S. J.;Chook, Y. M.;Look, A. T.
通讯作者：
Look, A. T.
影响因子：
7.5
作者：
Fischer, Melissa A.;Friedlander, Sharon Y.;Savona, Michael R.
通讯作者：
Savona, Michael R.
影响因子：
3.8
作者：
Crochiere M;Kashyap T;Kalid O;Shechter S;Klebanov B;Senapedis W;Saint-Martin JR;Landesman Y
通讯作者：
Landesman Y
影响因子：
20.3
作者：
Garzon, Ramiro;Savona, Michael;Stone, Richard
通讯作者：
Stone, Richard
DOI：
10.1534/g3.117.041277
发表时间：
2017-08-07
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Hart T;Tong AHY;Chan K;Van Leeuwen J;Seetharaman A;Aregger M;Chandrashekhar M;Hustedt N;Seth S;Noonan A;Habsid A;Sizova O;Nedyalkova L;Climie R;Tworzyanski L;Lawson K;Sartori MA;Alibeh S;Tieu D;Masud S;Mero P;Weiss A;Brown KR;Usaj M;Billmann M;Rahman M;Constanzo M;Myers CL;Andrews BJ;Boone C;Durocher D;Moffat J
通讯作者：
Moffat J