New therapeutic perspectives in CCDC6 deficient lung cancer cells (474 views)
Int J Cancer (ISSN: 0020-7136), 2015; 136(9): 2146-2157.
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Paper type: Journal Article,
Impact factor: 5.531, 5-year impact factor: 5.624
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84923212201&partnerID=40&md5=066c625f3467714bce439e2bb26ec1c3
Keywords: Candidate Biomarker, Ccdc6, Dna Damage And Homologousdirected Repair, Nsclc, Resistance To Platinum Salts And Parp-1 Inhibitor Sensitivity, Dna Damage And Homologous-Directed Repair, Cisplatin, Coiled Coil Domain Containing 6 Protein, Olaparib, Rad51 Protein, Tumor Suppressor Protein, Unclassified Drug, Adult, Article, Cancer Resistance, Disease Association, Disease Free Survival, Dna Repair, Drug Mechanism, Drug Potentiation, Drug Sensitization, Female, Homologous Recombination, Human, Human Cell, Human Tissue, Immunohistochemistry, Lung Cancer Cell Line, Lymph Node Metastasis, Non Small Cell Lung Cancer, Overall Survival, Priority Journal, Protein Deficiency, Protein Expression, Tissue Microarray,
Affiliations:
*** IBB - CNR ***
Istituto per l'Endocrinologia e l'Oncologia Sperimentale Gaetano Salvatore, CNR, IEOS, Via Pansini, 5Naples, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá Federico IINapoli, Italy
Dipartimento di Scienze Biomediche Avanzate, Universitá Federico IINapoli, Italy
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale A.CardarelliNapoli, Italy
CEINGE-Biotecnologie AvanzateNapoli, Italy
UOC Anatomia Patologica e Citopatologia, ISNT Fondazione G. PascaleNapoli, Italy
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham RoadLondon, United Kingdom
Department of Molecular Biology and Microbiology, College of Medicine, University of Central FloridaOrlando, FL, United States
References:
Not available.
Int J Cancer (ISSN: 0020-7136), 2015; 136(9): 2146-2157.
Export to BibTeX Export to EndNote
Paper type: Journal Article,
Impact factor: 5.531, 5-year impact factor: 5.624
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-84923212201&partnerID=40&md5=066c625f3467714bce439e2bb26ec1c3
Keywords: Candidate Biomarker, Ccdc6, Dna Damage And Homologousdirected Repair, Nsclc, Resistance To Platinum Salts And Parp-1 Inhibitor Sensitivity, Dna Damage And Homologous-Directed Repair, Cisplatin, Coiled Coil Domain Containing 6 Protein, Olaparib, Rad51 Protein, Tumor Suppressor Protein, Unclassified Drug, Adult, Article, Cancer Resistance, Disease Association, Disease Free Survival, Dna Repair, Drug Mechanism, Drug Potentiation, Drug Sensitization, Female, Homologous Recombination, Human, Human Cell, Human Tissue, Immunohistochemistry, Lung Cancer Cell Line, Lymph Node Metastasis, Non Small Cell Lung Cancer, Overall Survival, Priority Journal, Protein Deficiency, Protein Expression, Tissue Microarray,
Affiliations:
*** IBB - CNR ***
Istituto per l'Endocrinologia e l'Oncologia Sperimentale Gaetano Salvatore, CNR, IEOS, Via Pansini, 5Naples, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá Federico IINapoli, Italy
Dipartimento di Scienze Biomediche Avanzate, Universitá Federico IINapoli, Italy
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale A.CardarelliNapoli, Italy
CEINGE-Biotecnologie AvanzateNapoli, Italy
UOC Anatomia Patologica e Citopatologia, ISNT Fondazione G. PascaleNapoli, Italy
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham RoadLondon, United Kingdom
Department of Molecular Biology and Microbiology, College of Medicine, University of Central FloridaOrlando, FL, United States
References:
Not available.
New therapeutic perspectives in CCDC6 deficient lung cancer cells
Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p≤0.02) and negatively correlated to the disease free survival (p≤0.01) and the overall survival (p≤0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC. © 2014 UICC.
Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coildomain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p≤0.02) and negatively correlated to the disease free survival (p≤0.01) and the overall survival (p≤0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC. © 2014 UICC.
New therapeutic perspectives in CCDC6 deficient lung cancer cells
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