Evading p53 action during tumor development and therapy

Apoptosis is a regulated form of cell death that is important for normal development and tissue homeostasis. Senescence produces 'genetic death', in that the senescent cell is incapable of further propagation. Both processes are frequently disrupted in cancer cells, and each act as potent barriers to tumorigenesis. Since radiation and many chemotherapeutic agents induce apoptosis or senescence, the integrity of these programs can influence the outcome of cancer therapy. Our laboratory strives to understand how cancer genes control apoptosis and senescence in normal cells, and how mutations that disrupt these processes impact tumor development and therapy. The goal of these efforts is develop therapeutic strategies based on an understanding of drug action and cancer genotype. We currently are using genetically engineered mouse models to understand how apoptosis and senescence are controlled in tumor cells, as well as the response of tumors to conventional and targeted therapeutics. Recent work exploring the action of tumor-derived myc mutants in oncogenesis and the role of the p53 tumor suppressor network in the action of targeted therapeutics will be discussed.