Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer.
Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer.
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DOI：
10.1016/j.ccr.2013.01.015
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发表时间：
2013-03-18
期刊：
影响因子：
50.3
通讯作者：
Stegmaier K
中科院分区：
文献类型：
--
作者：
Roti G;Carlton A;Ross KN;Markstein M;Pajcini K;Su AH;Perrimon N;Pear WS;Kung AL;Blacklow SC;Aster JC;Stegmaier K
Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. SERCA calcium channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G0/G1 arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies “credential” SERCA as a therapeutic target in cancers associated with NOTCH1 mutations.
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