New therapeutic perspectives in CCDC6 deficient lung cancer cells
Corresponding Author
Francesco Morra
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
*F.M. and C.L. contributed equally to this work
Correspondence to: Angela Celetti, MD, PhD, Senior Staff Scientist, IEOS, CNR, Via Pansini, 5, 80131, Naples, Italy, E-mail : [email protected]Search for more papers by this authorChiara Luise
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
*F.M. and C.L. contributed equally to this work
Search for more papers by this authorRoberta Visconti
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Search for more papers by this authorStefania Staibano
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorFrancesco Merolla
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGennaro Ilardi
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGianluca Guggino
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorSimona Paladino
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
Search for more papers by this authorDaniela Sarnataro
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
CEINGE-Biotecnologie Avanzate, Napoli, Italy
Search for more papers by this authorRenato Franco
UOC Anatomia Patologica e Citopatologia, , ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorRoberto Monaco
UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorFederica Zitomarino
UOC Anatomia Patologica e Citopatologia, , ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorRoberto Pacelli
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGuglielmo Monaco
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorGaetano Rocco
UOC Chirurgia Toracica, ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorAniello Cerrato
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Search for more papers by this authorSpiros Linardopoulos
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom
Search for more papers by this authorMark T. Muller
Department of Molecular Biology and Microbiology, College of Medicine, University of Central Florida, Orlando, FL
Search for more papers by this authorCorresponding Author
Angela Celetti
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Correspondence to: Angela Celetti, MD, PhD, Senior Staff Scientist, IEOS, CNR, Via Pansini, 5, 80131, Naples, Italy, E-mail : [email protected]Search for more papers by this authorCorresponding Author
Francesco Morra
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
*F.M. and C.L. contributed equally to this work
Correspondence to: Angela Celetti, MD, PhD, Senior Staff Scientist, IEOS, CNR, Via Pansini, 5, 80131, Naples, Italy, E-mail : [email protected]Search for more papers by this authorChiara Luise
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
*F.M. and C.L. contributed equally to this work
Search for more papers by this authorRoberta Visconti
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Search for more papers by this authorStefania Staibano
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorFrancesco Merolla
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGennaro Ilardi
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGianluca Guggino
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorSimona Paladino
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
Search for more papers by this authorDaniela Sarnataro
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
CEINGE-Biotecnologie Avanzate, Napoli, Italy
Search for more papers by this authorRenato Franco
UOC Anatomia Patologica e Citopatologia, , ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorRoberto Monaco
UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorFederica Zitomarino
UOC Anatomia Patologica e Citopatologia, , ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorRoberto Pacelli
Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
Search for more papers by this authorGuglielmo Monaco
UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
Search for more papers by this authorGaetano Rocco
UOC Chirurgia Toracica, ISNT “Fondazione G. Pascale”, Napoli, Italy
Search for more papers by this authorAniello Cerrato
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Search for more papers by this authorSpiros Linardopoulos
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom
Search for more papers by this authorMark T. Muller
Department of Molecular Biology and Microbiology, College of Medicine, University of Central Florida, Orlando, FL
Search for more papers by this authorCorresponding Author
Angela Celetti
Istituto per l'Endocrinologia e l'Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
Correspondence to: Angela Celetti, MD, PhD, Senior Staff Scientist, IEOS, CNR, Via Pansini, 5, 80131, Naples, Italy, E-mail : [email protected]Search for more papers by this authorConflict of interest: The authors declare no conflict of interest.
Abstract
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-coil-domain 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.
Abstract
What's new?
Non-small cell lung cancer (NSCLC) is a deadly disease, with fewer than 15% of patients still alive five years post-diagnosis. But as this study suggests, predictive biomarkers could inform the development of much-needed novel therapeutic strategies. Defective expression of the tumor suppressor coiled-coil-domain containing 6 (CCDC6) was correlated with patient survival and, in NSCLC cells, was associated with deficient homology-directed repair (HDR), rendering the cells resistant to cisplatinum but sensitive to the PARP inhibitor olaparib. When given in combination, however, the two agents were synergistic. Thus, CCDC6 levels may offer valuable insight for therapeutic decisions in NSCLC.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| ijc29263-sup-0004-suppinfo3z.tif7.6 MB |
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| ijc29263-sup-0005-suppinfotabS1.pdf435.2 KB |
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