期刊
CANCER CELL
卷 23, 期 3, 页码 390-405出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.01.015
关键词
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资金
- Leukemia and Lymphoma Society (LLS)
- William Lawrence and Blanche Hughes Foundation
- SynCure Cancer Research Foundation
- National Cancer Institute [P01 CA 068484-11A1]
- European Hematology Association-American Society of Hematology International Fellowship Award
- American-Italian Cancer Foundation
- Lady Tata International Award for Research in Leukaemia
- LLS
- Fondazione Umberto Veronesi
- National Institutes of Health (NIH)/National Center for Research Resources [5 UL1 RR025758]
- NIH [R01 CA 092433]
- AULL (Associazione Umbra per lo studio e la terapia delle Leucemie e Linfomi)
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. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G(0)/G(1) 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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