New therapeutic perspectives in CCDC6 deficient lung cancer cells

    Authors

    F. Morra; C. Luise; R. Visconti; S. Staibano; F. Merolla; G. Ilardi; G. Guggino; S. Paladino; D. Sarnataro; R. Franco; R. Monaco; F. Zitomarino; R. Pacelli; G. Monaco; G. Rocco; A. Cerrato; S. Linardopoulos; M. T. Muller;A. Celetti

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    Abbreviated Journal Title

    Int. J. Cancer

    Keywords

    NSCLC; CCDC6; DNA damage and homologous-directed repair; candidate; biomarker; resistance to platinum salts and PARP-1 inhibitor sensitivity; HOMOLOGY-DIRECTED REPAIR; BRCA MUTATION CARRIERS; DNA-REPAIR; POLY(ADP-RIBOSE) POLYMERASE; SENSITIVITY; RET; ADENOCARCINOMA; CHEMOTHERAPY; RESISTANCE; INHIBITORS; Oncology

    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 (p0.02) and negatively correlated to the disease free survival (p0.01) and the overall survival (p0.05). 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. 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.

    Journal Title

    International Journal of Cancer

    Volume

    136

    Issue/Number

    9

    Publication Date

    1-1-2015

    Document Type

    Article

    Language

    English

    First Page

    2146

    Last Page

    2157

    WOS Identifier

    WOS:000349972300015

    ISSN

    0020-7136

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