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

Garry L Coles; Sandra Cristea; James T Webber; Rebecca S Levin; Steven M Moss; Andy He; Jaya Sangodkar; Yeonjoo C Hwang; Julia Arand; Alexandros P Drainas; Nancie A Mooney; Janos Demeter; Jessica N Spradlin; Brandon Mauch; Vicky Le; Yan Ting Shue; Julie H Ko; Myung Chang Lee; Christina Kong; Daniel K Nomura; Michael Ohlmeyer; Danielle L Swaney; Nevan J Krogan; Peter K Jackson; Goutham Narla; John D Gordan; Kevan M Shokat; Julien Sage

doi:10.1016/j.ccell.2020.05.003

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

Cancer Cell. 2020 Jul 13;38(1):129-143.e7. doi: 10.1016/j.ccell.2020.05.003. Epub 2020 Jun 11.

Authors

Garry L Coles¹, Sandra Cristea¹, James T Webber², Rebecca S Levin³, Steven M Moss⁴, Andy He¹, Jaya Sangodkar⁵, Yeonjoo C Hwang⁶, Julia Arand¹, Alexandros P Drainas¹, Nancie A Mooney⁷, Janos Demeter⁷, Jessica N Spradlin⁸, Brandon Mauch¹, Vicky Le¹, Yan Ting Shue¹, Julie H Ko¹, Myung Chang Lee¹, Christina Kong⁹, Daniel K Nomura¹⁰, Michael Ohlmeyer¹¹, Danielle L Swaney¹², Nevan J Krogan¹², Peter K Jackson¹³, Goutham Narla⁵, John D Gordan¹⁴, Kevan M Shokat³, Julien Sage¹⁵

Affiliations

¹ Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
² Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
³ 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.
⁴ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
⁵ Division of Genetic Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Baxter Laboratory, Stanford University, Stanford, CA 94305, USA; Department of Microbiology & Immunology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
⁹ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹⁰ 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.
¹¹ Icahn School of Medicine at Mount Sinai, New York, NY, USA; Atux Iskay LLC, Plainsboro, New Jersey, NJ 08536, USA.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ Department of Pediatrics, Stanford University, 265 Campus Drive, Stanford, CA 94305-5457, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: julsage@stanford.edu.

Abstract

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.

Keywords: GNAS; PKA; PP2A; SCLC; cancer; cancer stem cells; kinase; lung; neuroendocrine; phosphatase; proteomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

A549 Cells
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Chromogranins / genetics
Chromogranins / metabolism*
Cisplatin / administration & dosage
Cisplatin / pharmacology
Cyclic AMP-Dependent Protein Kinases / genetics
Cyclic AMP-Dependent Protein Kinases / metabolism*
GTP-Binding Protein alpha Subunits, Gs / genetics
GTP-Binding Protein alpha Subunits, Gs / metabolism*
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplastic Stem Cells / metabolism*
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism*
Proteomics / methods*
Signal Transduction / drug effects
Signal Transduction / genetics
Small Cell Lung Carcinoma / drug therapy
Small Cell Lung Carcinoma / genetics
Small Cell Lung Carcinoma / metabolism*
Xenograft Model Antitumor Assays / methods

Substances

Antineoplastic Agents
Chromogranins
Cyclic AMP-Dependent Protein Kinases
Protein Phosphatase 2
GNAS protein, human
GTP-Binding Protein alpha Subunits, Gs
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding