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

Giovanni Roti; Anne Carlton; Kenneth N Ross; Michele Markstein; Kostandin Pajcini; Angela H Su; Norbert Perrimon; Warren S Pear; Andrew L Kung; Stephen C Blacklow; Jon C Aster; Kimberly Stegmaier

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

机译：互补基因组筛选将SERCA确定为NOTCH1突变癌症的治疗靶标。

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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 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.

机译：Notch1是几种人类癌症中的合理治疗靶标，但作为转录调节剂，它对药物发现构成了挑战。为了鉴定Notch1调节剂，我们对带有白血病相关突变的NOTCH1等位基因的小分子抑制剂和cDNA增强子进行了两个基于细胞的高通量筛选。在这些互补筛的交叉点出现了Sarco /内质网钙ATP酶（SERCA）通道。 SERCA抑制会优先损害突变的Notch1受体的成熟和活性，并在NOTCH1突变的人类白血病细胞中诱导G0 / G1阻滞。一种小分子SERCA抑制剂在两种人类白血病小鼠模型中具有靶向活性，并干扰果蝇中的Notch信号传导。这些研究将“凭据” SERCA作为与NOTCH1突变相关的癌症的治疗靶标。

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《Cancer Cell》 |2013年第3期|共16页
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Giovanni Roti; Anne Carlton; Kenneth N Ross; Michele Markstein; Kostandin Pajcini; Angela H Su; Norbert Perrimon; Warren S Pear; Andrew L Kung; Stephen C Blacklow; Jon C Aster; Kimberly Stegmaier;
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1. Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer. [J] . Giovanni Roti, Anne Carlton, Kenneth N Ross, Cancer Cell . 2013,第3期

机译：互补基因组筛选将SERCA确定为NOTCH1突变癌症的治疗靶标。
2. Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. [J] . Giamas G, Filipovic A, Jacob J, Nature medicine . 2011,第6期

机译：对雌激素受体调节剂的基因组筛选确定LMTK3为乳腺癌的新治疗靶标。
3. Functional Genomic Screening Identifies USP11 as a Novel Therapeutic Target in Breast Cancer [J] . Dwane L., OConnor A. E., Mulrane L., Irish journal of medical science . 2016,第1期

机译：功能基因组筛选确定USP11为乳腺癌的新型治疗靶点。
4. Phage Display as a Tool for Development of Novel Therapeutics for Breast Cancer: Targeting Human Delta-Like Ligand1 Notch1 Ligand [C] . Joana Galvao, Margarida Silva, Maria Cabral, PEGS . 2014

机译：噬菌体展示作为乳腺癌新疗法的开发的工具：靶向人δ样的配体1 Notch1配体
5. Use of a transgenic mouse model of ovarian hyperstimulation to identify therapeutic targets and mechanisms in hormone-induced mammary cancer. [D] . Milliken, Erin Lee. 2005

机译：卵巢过度刺激转基因小鼠模型在荷尔蒙诱导的乳腺癌中鉴定治疗靶点和机制的用途。
6. Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer [O] . Giovanni Roti, Anne Carlton, Kenneth N. Ross, -1

机译：互补基因组屏幕识别sERCa作为治疗靶在NOTCH1突变癌症
7. Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer [O] . Roti Giovanni, Carlton Anne, Ross Kenneth N., 2013

机译：互补基因组筛选确定SERCA为NOTCH1突变癌症的治疗靶标
8. Parallel Genomic and Chemical Screens to Identify Both Therapeutic Targets and Inhibitors of These Targets in the Treatment of Neurofibromatosis [R] . Perrimon, N. 2006

机译：平行基因组和化学筛选，以确定这些目标的治疗目标和抑制剂治疗神经纤维瘤病

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

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