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Chromosomal aberrations in tumors often result in amplification, overexpression, or overactivation of oncogenic signaling pathways that can lead to unrestrained proliferation, a hallmark of cancer cells. Cancer cells can become reliant on this constitutive oncogenic activity to maintain high rates of proliferation and tolerance of genomic instability. DNA damage checkpoint pathways were found to act as an anti-cancer barrier in early human carcinogenesis, however, this endogenous defense against malignant transformation is compromised at advanced stages of tumorogenesis. The goal of this study was to determine if direct activation of DNA damage checkpoint pathways, in the absence of de novo DNA damage, could disrupt cancer maintenance and lead to selective killing of cancer cells. We found that activation of checkpoint kinase 2 (Chk2) by expression-induced autophosphorylation, led to cell death in multiple cancer cell lines,independent of p53 status, while there was little cell death detected following expression of Chk2 in non-transformed cell lines. We also examined the anti-tumor activity of Chk2 in a human colon cancer xenograft model using a tetracycline inducible Chk2 cell line. Activation of Chk2 in vivo showed potent growth inhibition of pre-established tumors derived from a Chk2-inducible Dld1 colon cancer cell line. Furthermore, we found that small molecule Chk2 activators could recapitulate the anti-cancer phenotypes observed following Chk2 expression. Selective toxicity, the guiding principle for chemotherapy, has typically been achieved by inhibiting a biological pathway. Here we demonstrate that we can achieve selective toxicity through activation of a biological pathway and that DNA damage checkpoint pathways may protect against cancer epigenetically after malignant transformation by antagonizing oncogenes and tumor maintenance.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA