Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer

被引：123

作者：

Roti, Giovanni ^{[1
,3
]}

Carlton, Anne ^{[1
,3
]}

Ross, Kenneth N. ^{[4
]}

Markstein, Michele ^{[5
]}

Pajcini, Kostandin ^{[6
,7
]}

Su, Angela H. ^{[1
,3
]}

Perrimon, Norbert ^{[8
,11
]}

Pear, Warren S. ^{[6
,7
]}

Kung, Andrew L. ^{[12
]}

Blacklow, Stephen C. ^{[2
,9
]}

Aster, Jon C. ^{[10
]}

Stegmaier, Kimberly ^{[1
,3
,4
]}

机构：

[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Canc Biol Program, Boston, MA 02215 USA

[3] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[4] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

[5] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA

[6] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[8] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA

[12] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA

来源：

CANCER CELL | 2013年 / 23卷 / 03期

基金：

美国国家卫生研究院;

关键词：

SQUAMOUS-CELL TUMORS; C-MYC; MUTATIONS; GENE; LEUKEMIA; ACTIVATION; PRESENILIN; EXPRESSION; RECEPTOR; ATP2A2;

D O I：

10.1016/j.ccr.2013.01.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：390 / 405

页数：16

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