Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Chordomas are rare bone tumors with limited treatment strategies.
• Genomic analysis is crucial for understanding tumor biology and identifying therapeutic vulnerabilities.

Purpose of the Study:

• To investigate the genomic landscape of advanced chordomas.
• To identify potential therapeutic targets and mechanisms of resistance.

Main Methods:

• Whole-exome and whole-genome sequencing of advanced chordoma samples (n=11).
• Analysis of mutational signatures and genomic instability.
• Clinical evaluation of PARP inhibitor olaparib in a patient with refractory chordoma.

Main Results:

• Genomic patterns indicative of homologous recombination (HR) DNA repair deficiency were identified in advanced chordomas.
• Enrichment of an HR deficiency mutational signature (72.7% of samples) correlated with genomic instability.
• A patient with refractory chordoma experienced prolonged benefit from olaparib, with subsequent analysis revealing a PARP1 mutation upon progression.

Conclusions:

• Defective HR DNA repair is a potential therapeutic vulnerability in chordoma.
• PARP inhibitors represent a promising treatment avenue for chordoma.
• Understanding PARP inhibitor resistance mechanisms, such as PARP1 mutations, is critical for optimizing treatment outcomes.