Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors

Cancer Cell. 2020 Dec 14;38(6):844-856.e7. doi: 10.1016/j.ccell.2020.10.009. Epub 2020 Nov 12.

Abstract

Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.

Keywords: CXorf67; PALB2; PARP inhibitors; ependymoma tumor; homologous recombination repair; radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA2 Protein / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chemoradiotherapy
  • Ependymoma / genetics
  • Ependymoma / metabolism
  • Ependymoma / therapy*
  • Fanconi Anemia Complementation Group N Protein / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Infratentorial Neoplasms / genetics
  • Infratentorial Neoplasms / metabolism
  • Infratentorial Neoplasms / therapy*
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Recombinational DNA Repair / drug effects
  • Recombinational DNA Repair / radiation effects
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • BRCA2 Protein
  • BRCA2 protein, human
  • EZHIP protein, human
  • Fanconi Anemia Complementation Group N Protein
  • Oncogene Proteins
  • PALB2 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors