Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer

  • NPJ Precis Oncol. 2024 Dec 26;8(1):291. doi: 10.1038/s41698-024-00777-6.
Katerina Tsilingiri  #  1 ,  Anna Chalari  #  1 ,  Georgia Christopoulou  2 ,  Alexandra Voutsina  3 ,  Pantelis Constantoulakis  2 ,  Κonstantinos Potaris  4 ,  Ioannis Vamvakaris  5 ,  Dora Hatzidaki  6 ,  Georgina Zachou  6 ,  Giannis Vatsellas  7 ,  Vassilis Georgoulias  6 ,  Athanasios Kotsakis  8 ,  Apostolos Klinakis  9
Affiliations
  • 1. Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 2. Genotypos MSA, Private Molecular Biology and Cytogenetics Diagnostic Center, Athens, Greece.
  • 3. Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece.
  • 4. Department of Thoracic Surgery, "SOTIRIA" General Hospital, Athens, Greece.
  • 5. Department of Pathology, "SOTIRIA" General Hospital, Athens, Greece.
  • 6. Hellenic Oncology Research Group, Athens, Greece.
  • 7. Greek Genome Centre, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 8. Department of Medical Oncology, University General Hospital of Larisa, Larisa, Greece.
  • 9. Biomedical Research Foundation of the Academy of Athens, Athens, Greece. [email protected].
  • # Contributed equally.
PMID: 39725687 DOI: 10.1038/s41698-024-00777-6
Abstract

PARP inhibitors (PARPi) have shown efficacy in tumours harbouring mutations in homologous recombination repair (HRR) genes. Somatic HRR mutations have been described in patients with Non-Small Cell Lung Cancer (NSCLC), but PARP inhibitors (PARPi) are not yet a therapeutic option. Here we assessed the homologous recombination status of early-stage NSCLC and explored the therapeutic benefit of PARPi in preclinical models. The Genomic Scarring Score GSS (GSS) and HRR mutation profile of 136 patients were assessed. High GSS (h-GSS) was observed in 39 (28.7%) patients half of which carried pathogenic/likely pathogenic somatic HRR mutations. TP53 mutations were significantly enriched in h-GSS tumours (p < 0.001). Olaparib significantly delayed tumour growth in h-GSS but not l-GSS Patient-derived Xenografts (PDXs), while patients with h-GSS/TP53mut tumours respond favourably to Adjuvant platinum-based chemotherapy. Our functional data clearly support the idea that the use of GSS rather than the mutational status of HRR genes could select patients for administration of PARPi.

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