CHK-2 expression in lung cancer and tumor sensitivity to DNA damage-inducing therapy

Abstract

7247 Background: Check-point kinase-2 (CHK2 kinase) is a critical intermediate in DNA damage pathway that regulates cell cycle progression, DNA repair and apoptosis. CHK2 gene mutation has been linked to familial human cancer syndrome Li-Fraumeni syndrome. Genetically, CHK2 knockout mice are remarkably resistant to ionizing radiation. The main purpose of this study was to correlate the expression level of CHK2 kinase in non-small cell lung cancer (NSCLC) with tumor response to DNA damaging agents. Methods: We compared the CHK-2 expression levels in NSCLC, ovarian cancer, SCLC, normal pulmonary epithelial cell lines and studied the role of epigenetic mechanism in controlling CHK2 expression. In our in-vivo studies, we used tissue micro-arrays and IHC to quantify CHK2 expression in common carcinomas. We reviewed the clinical data of 46 patients with advanced NSCLC, quantified CHK2 and p53 expression by IHC method and assessed clinical response by radiographic imaging. We correlated the tumor sensitivity to DNA damage-inducing therapies, such as chemo and radiation therapy with the level of CHK2 kinase in these tumors. Results: We found that CHK2 kinase expression was low to absent in NSCLC cell line but present in other cell lines. The reduced CHK2 expression appears due to methylation of the CHK2 promoter. CHK2 expression was present in 88% of seminoma and in 17% of NSCLC samples, tumors known to be highly sensitive and resistant, respectively, to DNA damaging agents. Our data showed that the clinical responses of NSCLC were highly variable. There appeared to be no correlation between CHK2 and p53 expression and tumor sensitivity to chemotherapy and/or radiation. Conclusions: Although CHK2 kinase is aberrantly expressed in NSCLC, there appeared to be no correlation between the tumor response and the level of CHK2 expression. Genetic complexity of advanced NSCLC may abrogate the effect of single gene expression on tumor sensitivity to treatment. Further studies using combinatorial approach should be considered. No significant financial relationships to disclose.