Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells

Overexpression of the erbB-2 tyrosine kinase receptor, p185(crbB-2), is a c ommon alteration in non-small cell lung cancer (NSCLC) and has been associa ted with poor prognosis and a tumor drug resistance phenotype, In this stud y, we have examined the consequences of crbB-2 depletion on DNA repair, cel l cycle, and apoptosis using a panel of NSCLC cell lines constitutively ove rexpressing er erbB-2 receptor. Depletion of the erbB-2 was achieved using the tyrosine kinase inhibitor CP127,374 which promotes erbB-2 degradation. Treatment with CP127,374 concentrations which deplete erbB-2 and inhibit ty rosine phosphorylation resulted in downregulation of DNA repair mechanisms and cell accumulation at G1 phase of the cell cycle. G1 arrest was observed in cells with mutated p53 as well as cells lacking p53 protein, suggesting a p53-independent mechanisms, NSCLC cells which overexpress erbB-2 were mo re resistant to cisplatin-induced cytotoxicity in comparison to cells expre ssing low levels of erbB-2. Treatment with CP127,374 alone did not result i n any induction of apoptosis, A combination of CP127,374 and cisplatin, how ever, was more potent in cell growth inhibition and induction of apoptosis compared to treatment with cisplatin alone. Together, our results further s upport a pivotal role of erbB-2 signaling in the regulatory balance between DNA repair, cell cycle checkpoints and apoptosis; all these mechanisms are essential determinants for tumor cell destiny following chemotherapy stres s.