CDC7 kinase in normal and cancer cells: potential implications for cancer treatment

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Project Summary/Abstract This proposal focuses on cell division cycle 7-related protein (CDC7). The overarching goal of this proposal is to test whether inhibition of CDC7 kinase might represent a powerful therapeutic strategy in treatment of human cancers carrying mutated p53 protein. In our study, we will utilize human cancer cell lines as well as a mouse cancer model. Our work may lead to a novel therapeutic approach for cancer patients, specifically targeting p53-mutated human cancer cells. CDC7 is a cell cycle kinase that is activated through a physical interaction with regulatory subunits, DBF4 or DRF1. DRF1 represents the activator of CDC7 during embryogenesis, while DBF4 functions mainly during divisions of somatic cells. The DBF4-CDC7 kinase becomes activated at the end of G1 phase and phosphorylates components of the pre-replication complexes (pre-RCs), thereby triggering entry of cells into DNA synthesis phase (S phase). CDC7 was reported to be essential for cell division in all organisms studied, from yeast to humans. Several reports documented that human cancer cells with mutated p53 are particularly sensitive to CDC7 inhibition. Depletion of CDC7 protein, or inhibition of its kinase activity in p53-mutant cancer cells was shown to trigger tumor cell apoptosis. For these reasons, we decided to further study the CDC7 protein and its role in normal cell proliferation as well as in tumorigenesis. Previous work by others has established that CDC7 knockout mice die very early during gestation, thereby precluding analyses of CDC7 in an adult organism. To circumvent this limitation, and to study CDC7 function at later stages, our laboratory developed a novel mouse strain that allows us to turn off CDC7 protein. These mice and cells derived from them offer us tools to study the molecular functions of CDC7. In Aim 1, we will study the molecular role of CDC7 in cell division of normal, non-transformed cells. Our preliminary results indicate the presence of a novel, previously unanticipated molecular mechanism of cell division, which will be examined in this Aim. In Aim 2, we will analyze additional functions of CDC7 in human cancer cells, through which CDC7 may play important roles in tumorigenesis. In Aim 3, we will utilize a mouse model that faithfully recapitulates p53-mutant triple-negative breast cancers. Using these mice, we will test the requirement for CDC7 during tumorigenesis. The expected overall impact of this proposal is that it will change our understanding of mechanisms governing cell division, will elucidate novel roles of CDC7 in tumorigenesis, and will test the utility of targeting CDC7 in cancer treatment.