Protein kinase Cι and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities

We report that atypical protein kinase Cι (PKCι) is an oncogenic driver of glioblastoma (GBM). Deletion or inhibition of PKCι significantly impairs tumor growth and prolongs survival in murine GBM models. GBM cells expressing elevated PKCι signaling are sensitive to PKCι inhibitors, whereas those expressing low PKCι signaling exhibit active SRC signaling and sensitivity to SRC inhibitors. Resistance to the PKCι inhibitor auranofin is associated with activated SRC signaling and response to a SRC inhibitor, whereas resistance to a SRC inhibitor is associated with activated PKCι signaling and sensitivity to auranofin. Interestingly, PKCι- and SRC-dependent cells often co-exist in individual GBM tumors, and treatment of GBM-bearing mice with combined auranofin and SRC inhibitor prolongs survival beyond either drug alone. Thus, we identify PKCι and SRC signaling as distinct therapeutic vulnerabilities that are directly translatable into an improved treatment for GBM. [Display omitted] •PKCι is an oncogenic driver of GBM that confers response to PKCι inhibitor therapy•GBMs can be classified into mutually exclusive PKCι- or SRC-dependent subtypes•PKCι- and SRC-dependent cells often co-exist in single GBM tumors•Combined PKCι and SRC inhibition is an effective treatment strategy for GBM Kenchappa et al. demonstrate that the tumor cells that comprise a glioblastoma, the most common and lethal of brain tumors, can be distinguished by how they depend on two oncogenic kinases: PKCι and SRC.