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

Rajappa S. Kenchappa, Yi Liu, Michael G. Argenziano, Matei A. Banu, Ann C. Mladek, Rita West, Amanda Luu, Alfredo Quiñones-Hinojosa, Dolores Hambardzumyan, Verline Justilien, Michael Leitges, Jann N. Sarkaria, Peter A. Sims, Peter Canoll, Nicole R. Murray, Alan P. Fields, Steven S. Rosenfeld

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number110054
JournalCell reports
Volume37
Issue number8
DOIs
StatePublished - Nov 23 2021

Keywords

  • SRC
  • glioblastoma
  • kinase inhibitor
  • protein kinase C iota

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Protein kinase C<sub>ι</sub> and SRC signaling define reciprocally related subgroups of glioblastoma with distinct therapeutic vulnerabilities'. Together they form a unique fingerprint.

Cite this