Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer
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 as...
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Nature Portfolio
2024-12-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-024-00777-6 |
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| author | Katerina Tsilingiri Anna Chalari Georgia Christopoulou Alexandra Voutsina Pantelis Constantoulakis Κonstantinos Potaris Ioannis Vamvakaris Dora Hatzidaki Georgina Zachou Giannis Vatsellas Vassilis Georgoulias Athanasios Kotsakis Apostolos Klinakis |
| author_facet | Katerina Tsilingiri Anna Chalari Georgia Christopoulou Alexandra Voutsina Pantelis Constantoulakis Κonstantinos Potaris Ioannis Vamvakaris Dora Hatzidaki Georgina Zachou Giannis Vatsellas Vassilis Georgoulias Athanasios Kotsakis Apostolos Klinakis |
| author_sort | Katerina Tsilingiri |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a0e3cc1fdeee4fee89cce16833de9504 |
| institution | DOAJ |
| issn | 2397-768X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-a0e3cc1fdeee4fee89cce16833de95042025-08-20T02:57:39ZengNature Portfolionpj Precision Oncology2397-768X2024-12-018111110.1038/s41698-024-00777-6Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancerKaterina Tsilingiri0Anna Chalari1Georgia Christopoulou2Alexandra Voutsina3Pantelis Constantoulakis4Κonstantinos Potaris5Ioannis Vamvakaris6Dora Hatzidaki7Georgina Zachou8Giannis Vatsellas9Vassilis Georgoulias10Athanasios Kotsakis11Apostolos Klinakis12Biomedical Research Foundation of the Academy of AthensBiomedical Research Foundation of the Academy of AthensGenotypos MSA, Private Molecular Biology and Cytogenetics Diagnostic CenterInstitute of Chemical Biology, National Hellenic Research FoundationGenotypos MSA, Private Molecular Biology and Cytogenetics Diagnostic CenterDepartment of Thoracic Surgery, “SOTIRIA” General HospitalDepartment of Pathology, “SOTIRIA” General HospitalHellenic Oncology Research GroupHellenic Oncology Research GroupGreek Genome Centre, Biomedical Research Foundation of the Academy of AthensHellenic Oncology Research GroupDepartment of Medical Oncology, University General Hospital of LarisaBiomedical Research Foundation of the Academy of AthensAbstract 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.https://doi.org/10.1038/s41698-024-00777-6 |
| spellingShingle | Katerina Tsilingiri Anna Chalari Georgia Christopoulou Alexandra Voutsina Pantelis Constantoulakis Κonstantinos Potaris Ioannis Vamvakaris Dora Hatzidaki Georgina Zachou Giannis Vatsellas Vassilis Georgoulias Athanasios Kotsakis Apostolos Klinakis Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer npj Precision Oncology |
| title | Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer |
| title_full | Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer |
| title_fullStr | Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer |
| title_full_unstemmed | Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer |
| title_short | Genomic scarring score predicts the response to PARP inhibitors in non-small cell lung cancer |
| title_sort | genomic scarring score predicts the response to parp inhibitors in non small cell lung cancer |
| url | https://doi.org/10.1038/s41698-024-00777-6 |
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