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

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Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells.
Cancer Cell ( IF 50.3 ) Pub Date : 2020-06-11 , DOI: 10.1016/j.ccell.2020.05.003
Garry L Coles ₁ , Sandra Cristea ₁ , James T Webber ₂ , Rebecca S Levin ₃ , Steven M Moss ₄ , Andy He ₁ , Jaya Sangodkar ₅ , Yeonjoo C Hwang ₆ , Julia Arand ₁ , Alexandros P Drainas ₁ , Nancie A Mooney ₇ , Janos Demeter ₇ , Jessica N Spradlin ₈ , Brandon Mauch ₁ , Vicky Le ₁ , Yan Ting Shue ₁ , Julie H Ko ₁ , Myung Chang Lee ₁ , Christina Kong ₉ , Daniel K Nomura ₁₀ , Michael Ohlmeyer ₁₁ , Danielle L Swaney ₁₂ , Nevan J Krogan ₁₂ , Peter K Jackson ₁₃ , Goutham Narla ₅ , John D Gordan ₁₄ , Kevan M Shokat ₃ , Julien Sage ₁

Affiliation

Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Icahn School of Medicine at Mount Sinai, New York, NY, USA; Atux Iskay LLC, Plainsboro, New Jersey, NJ 08536, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; David J. Gladstone Institute, University of California San Francisco, San Francisco, CA 94158, USA.
Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA.

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 α 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.

中文翻译：

无偏蛋白质组分析在小细胞肺癌干细胞中发现了可靶向的GNAS / PKA / PP2A轴。

使用无偏激酶分析，我们确定蛋白激酶A（PKA）为小细胞肺癌（SCLC）中的活性激酶。通过活化PP2A磷酸酶在遗传上或药理上抑制PKA活性，可抑制SCLC在培养物中和体内的扩增。相反，GNAS（G蛋白α亚基）是在人类SCLC的一小部分中被遗传激活的PKA激活剂，可促进SCLC的发展。磷酸蛋白质组学分析确定了许多PKA底物和作用机理。特别地，在移植研究中，PKA活性是SCLC干细胞繁殖所必需的。顽固性癌症的广泛蛋白质组学分析有可能发现可靶向的信号网络，例如SCLC中的GNAS / PKA / PP2A轴。

更新日期：2020-07-13

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