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.