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

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Publication Year:
2020
Authors:
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
PubMed ID:
32531271
Funding Grants:
Public Summary:
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.
Scientific 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 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.