Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells

被引：72

作者：

Coles, Garry L. ^{[1
,2
]}

Cristea, Sandra ^{[1
,2
]}

Webber, James T. ^{[3
]}

Levin, Rebecca S. ^{[4
,5
]}

Moss, Steven M. ^{[5
]}

He, Andy ^{[1
,2
]}

Sangodkar, Jaya ^{[6
]}

Hwang, Yeonjoo C. ^{[7
]}

Arand, Julia ^{[1
,2
]}

Drainas, Alexandros P. ^{[1
,2
]}

Mooney, Nancie A. ^{[8
,9
]}

Demeter, Janos ^{[8
,9
]}

Spradlin, Jessica N. ^{[10
]}

Mauch, Brandon ^{[1
,2
]}

Le, Vicky ^{[1
,2
]}

Shue, Yan Ting ^{[1
,2
]}

Ko, Julie H. ^{[1
,2
]}

Lee, Myung Chang ^{[1
,2
]}

Kong, Christina ^{[11
]}

Nomura, Daniel K. ^{[10
,12
,13
]}

Ohlmeyer, Michael ^{[14
,15
]}

Swaney, Danielle L. ^{[5
,16
,17
]}

Krogan, Nevan J. ^{[5
,16
,17
]}

Jackson, Peter K. ^{[8
,9
]}

Narla, Goutham ^{[6
]}

Gordan, John D. ^{[7
]}

Shokat, Kevan M. ^{[4
,5
]}

Sage, Julien ^{[1
,2
]}

机构：

[1] Stanford Univ, Dept Pediat, 265 Campus Dr, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[3] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[6] Univ Michigan, Michigan Med, Div Genet Med, Ann Arbor, MI 48109 USA

[7] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Med, San Francisco, CA 94143 USA

[8] Stanford Univ, Baxter Lab, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Microbiol Immunol, Stanford, CA 94305 USA

[10] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA

[11] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[12] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[13] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

[14] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[15] Atux Iskay LLC, Plainsboro, NJ 08536 USA

[16] Univ Calif San Francisco, Quantitat Biosci Inst QBI, San Francisco, CA 94158 USA

[17] Univ Calif San Francisco, David J Gladstone Inst, San Francisco, CA 94158 USA

来源：

CANCER CELL | 2020年 / 38卷 / 01期

关键词：

PROTEIN PHOSPHATASE 2A; REGULATORY SUBUNIT; CATALYTIC SUBUNIT; GENOMIC ANALYSIS; KINASE; MUTATIONS; IDENTIFICATION; GENE; PATHWAY; ACTIVATION;

D O I：

10.1016/j.ccell.2020.05.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein alpha subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

引用

页码：129 / +

页数：22

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