J Michels1, J Adam2, A Goubar3, F Obrist4, D Damotte5, A Robin3, M Alifano6, I Vitale7, K A Olaussen8, P Girard9, I Cremer10, M Castedo4, J-C Soria11, G Kroemer12. 1. INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Department of Medical Oncology, Gustave Roussy Comprehensive Cancer Center, Villejuif Paris-Sud University, Villejuif. 2. Paris-Sud University, Villejuif Department of Pathology, Gustave Roussy Comprehensive Cancer Center, Villejuif INSERM U981, Villejuif. 3. INSERM U981, Villejuif. 4. INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris. 5. INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Department of Pathology and Thoracic Surgery, Cochin Hospital, AP-HP, Paris Paris Descartes University, Paris, France. 6. Department of Pathology and Thoracic Surgery, Cochin Hospital, AP-HP, Paris Paris Descartes University, Paris, France. 7. Regina Elena National Cancer Institute, Rome Department of Biology, University of Rome 'TorVergata', Rome, Italy. 8. Paris-Sud University, Villejuif INSERM U981, Villejuif. 9. Thoracic Department, Mutualiste Montsouris Institute, Paris. 10. INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Paris Descartes University, Paris, France. 11. Paris-Sud University, Villejuif INSERM U981, Villejuif Department of Drug Development, Gustave Roussy Comprehensive Cancer Center, Villejuif. 12. INSERM UMR1138 Group 11, Cordeliers Research Centre, Paris Pierre and Marie Curie University, Paris Paris Descartes University, Paris, France Metabolomics Platform, Gustave Roussy Comprehensive Cancer Center, Villejuif Department of Biology, Georges Pompidou European Hospital, AP-HP, Paris, France kroemer@orange.fr.
Abstract
BACKGROUND: Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC. PATIENTS AND METHODS: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC. RESULTS: Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification. CONCLUSION: NSCLC patients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.
BACKGROUND:Cisplatin-resistant non-small cell lung cancer (NSCLC) cells are often characterized by alterations in vitamin B-related metabolic processes, including the overexpression and hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1) and the downregulation of pyridoxal kinase (PDXK), correlating with elevated apoptosis resistance. Low PDXK expression is an established negative prognostic factor in NSCLC. PATIENTS AND METHODS: We determined by immunohistochemistry the expression of PARP1 and the level of its product, poly(ADP-ribose) (PAR), in two independent cohorts of patients with resected NSCLC. RESULTS: Intratumoral high levels (above median) of PAR (but not PARP1 protein levels) had a negative prognostic impact in both the training (92 stage I subjects) and validation (133 stage I and II subjects) cohorts, as determined by univariate and multivariate analyses. The simultaneous assessment of PAR and PDXK protein levels improved risk stratification. CONCLUSION:NSCLCpatients with high intratumoral PARP1 activity (i.e. elevated PAR levels above median) and low PDXK expression (below median) had a dismal prognosis, while patients with low PARP1 activity and high PDXK expression had a favorable outcome. Altogether, these results underscore the clinical potential and possible therapeutic relevance of these biomarkers.
Authors: Susanne Kossatz; Brandon Carney; Melanie Schweitzer; Giuseppe Carlucci; Vesselin Z Miloushev; Uday B Maachani; Prajwal Rajappa; Kayvan R Keshari; David Pisapia; Wolfgang A Weber; Mark M Souweidane; Thomas Reiner Journal: Cancer Res Date: 2017-01-20 Impact factor: 12.701
Authors: Paula Demétrio de Souza França; Susanne Kossatz; Christian Brand; Daniella Karassawa Zanoni; Sheryl Roberts; Navjot Guru; Dauren Adilbay; Audrey Mauguen; Cristina Valero Mayor; Wolfgang A Weber; Heiko Schöder; Ronald A Ghossein; Ian Ganly; Snehal G Patel; Thomas Reiner Journal: Eur J Nucl Med Mol Imaging Date: 2021-05-05 Impact factor: 10.057