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

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. [Display omitted] •PKA inhibition or PP2A activation inhibits SCLC growth•The GNAS/PKA axis promotes SCLC growth•Proteomics studies uncover widespread PKA targets and downstream signaling networks•PKA activation promotes a cancer stem cell state Using a combination of pre-clinical models and phosphoproteomics, Coles et al. identify protein kinase A (PKA) and molecules in the PKA signaling pathway as key regulators of small cell lung cancer initiation and progression.