Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Nat Commun. 2019 Apr 9;10(1):1635. doi: 10.1038/s41467-019-09633-9.

Abstract

Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Chordoma / drug therapy*
  • Chordoma / genetics
  • Chordoma / pathology
  • Chromosome Mapping
  • DNA Breaks, Double-Stranded
  • DNA Mutational Analysis
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Genomic Instability
  • Humans
  • Male
  • Middle Aged
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use*
  • Piperazines / pharmacology
  • Piperazines / therapeutic use*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Precision Medicine / methods
  • Protein Domains / genetics
  • Recombinational DNA Repair / genetics*
  • Treatment Outcome
  • Whole Exome Sequencing

Substances

  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • olaparib