Head and neck cancer is believed to originate via a multi-step process that involves the activation of oncogenes and inactivation of tumor suppressor genes, however, the specific pattern of progression and the necessary genetic alterations have not been delineated. Although treatment advances have been made in the last 30 years, little or no survival improvement has been obtained. Identifying the specific genes or proteins involved in transformation of a normal cell to a malignant cell, and the particular sequence of these genes or proteins, is necessary for the development of early detection methods, the formulation of new treatment strategies, and the prediction of patient outcome. While studies on oral tumorigenesis are specifically beneficial to head and neck cancer patients, such studies are likely to also aid the understanding of multi-step carcinogenesis in general. To translate these advantages into procedures that may be beneficial to oral cancer patients, the basic molecular changes involved in oral cancer development must be understood. To this end we investigated the mechanism of cell cycle dysregulation in oral cancer development. As with most human tumors, the common tumor suppressor p53 (but not its regulator pl4ARF) and the pRb pathway are disrupted in oral cancer cells. Most interestingly, we found that the pRb regulator cdk6 is preferentially hyperactivated in oral cancer cells by a variety of mechanisms, while the related kinase cdk4 is active at levels similar to those observed in primary cells. These data complement a number of studies in our labs and others that indicate that cdk4 and cdk6 are not equivalent in their ability to induce proliferation in all cell types and may have non-overlapping roles in tumorigenesis. Further, inhibition of both kinases by p 16INK4a can lead to a senescent state in oral cancer cell lines, indicating that continued activity of cdk4, cdk6 or both is required for tumor cell proliferation. In order to better understand the roles of these pRb pathway regulators and the process of cell cycle dysregulation in general in oral cancer, we propose three specific aims: (1) construct and deconstruct oral cancer cells by manipulating the activity of cell cycle regulators in normal oral epithelial cells and oral cancer cells respectively. This will test suspected targets for antiproliferative agents in oral cancer cells and will elucidate the consequences of dysregulation of known cell cycle regulators. (2) Reversibly inhibit cdk4, cdk6 or both in order to induce senescence and apoptosis in oral cancer cells and thus validate them as targets for therapy. (3) Determine the biological activity of CLLL7, a novel cdk4/cdk6 interacting protein encoded by a gene on chromosome 13.
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