Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma

Syed A. Ali, Verline Justilien, Lee Jamieson, Nicole R Murray, Alan P Fields

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

We report that the protein kinase Cι (PKCι) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCι activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCι-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCι and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCι-ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC. Ali et al. show that in KRAS-mediated lung adenocarcinoma, PKCι controls NOTCH3 expression by phosphorylating ELF3 and driving occupancy at the NOTCH3 promoter. PKCι-ELF3-NOTCH3 signaling controls the TIC phenotype and combined blockade of PKCι and NOTCH has a synergistic antitumor effect in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)367-378
Number of pages12
JournalCancer Cell
Volume29
Issue number3
DOIs
StatePublished - Mar 14 2016

Keywords

  • ELF3
  • KRAS-driven lung adenocarcinoma
  • NOTCH signaling
  • Protein kinase Cι
  • Therapeutic intervention

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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