PKCα as a signaling gatekeeper upstream of mTORC1 in mEGFR NSCLC

Despite decades of research since phorbol esters first linked protein kinase C (PKC) to tumor promotion, the biological role of this family of kinases in cancer has remained ambiguous because of isozyme-specific functions and tissue-type-dependent effects. Here, we delineate critical roles for PKC in lung cancer. We previously showed that sustained activation of PKCβ_II activates mTOR, an effect evident in lung cancer cell lines with high expression of classical PKCs (cPKCs). These findings prompted us to examine lung cancers driven by mutant EGFR (mEGFR), in which PKCα is highly expressed. We find that mEGFR-dependent activation of PKCα drives serum-deprived proliferation, anchorage-independent growth (AIG), and anchorage-independent survival (AIS). Subsequent studies revealed that the mutant receptor is impaired in ligand-independent activation and, due to altered autophosphorylation, exhibits biased activation of the PLC arm, preferentially propagating signals through a PLC-PKCα-AKT-mTORC1 axis required for AIG and AIS. In parallel, we investigated the basis of PKCα upregulation and found that elevated PKCα levels are independent of mEGFR. Bioinformatic analysis of mEGFR lung cancers highlighted basal cells, a subtype of lung cell which intrinsically express high PRKCA, as the likely cell-of-origin, suggesting that cell lineage sets a high ceiling for PKCα abundance, while mEGFR licenses the activation of the kinase. Collectively, these data define a pathway-specific role for cPKCs, particularly PKCα, as upstream effectors of mTORC1 in mEGFR systems, establishing a neomorphic dependency on the PKCα-AKT-mTORC1 signaling arm that sustains tumorigenesis via biased signaling by the mutant receptor.