Negative prognostic value of high levels of intracellular poly(ADP-ribose) in non-small cell lung cancer

• Published in: Annals of oncology Vol. 26; no. 12; pp. 2470 - 2477
• Main Authors: Michels, J., Adam, J., Goubar, A., Obrist, F., Damotte, D., Robin, A., Alifano, M., Vitale, I., Olaussen, K.A., Girard, P., Cremer, I., Castedo, M., Soria, J.-C., Kroemer, G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2015
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - biosynthesis; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - metabolism; Cohort Studies; Female; Follow-Up Studies; Humans; Intracellular Fluid - metabolism; Lung Neoplasms - diagnosis; Lung Neoplasms - metabolism; Male; Middle Aged; niacin; nicotinamide adenine dinucleotide; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose - biosynthesis; poly ADP-ribosylation; Poly(ADP-ribose) Polymerases - biosynthesis; Prognosis; prognostic biomarker; vitamin B6; nicotinamide adenine dinucleotide; niacin; vitamin B6; prognostic biomarker; poly ADP-ribosylation
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1093/annonc/mdv393

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. 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. 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. 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.