A PKA/PP2A AXIS DRIVES THE GROWTH OF NEUROENDOCRINE SCLC

Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer whose biology is still poorly understood. Using a multiplexed inhibitor beads assay, we identified active kinases in SCLC. Among those, we found that PKA is critical for the expansion of SCLC in culture and in vivo. PKA promotes the neuroendocrine epithelial state associated with SCLC tumor-initiating cells. Phosphoproteomics analyses identify ~200 PKA substrates and show that PKA controls multiple facets of SCLC growth. Notably, the PP2A phosphatase counteracts the oncogenic effects of PKA, and PP2A activators inhibit SCLC as single agents and with chemotherapy. Our data uncover key signaling networks in SCLC and indicate that targeting the PKA/PP2A pathway may help inhibit this lethal neuroendocrine cancer. H29 and 82 cells were infected with a lentivirus to express either a dox inducible GFP (control) of active form of PRKACA (aPKA). Puromycin resistant cells were injected into NSG mice and animals were given doxycycline (2mg/ml) in the drinking water.