The successful combinations attempt to support HDM2 antagonists most often by inducing natural DNA damage signaling (achieved with DNA-damaging chemical agents or irradiation), blocking pro-survival or p53-inhibitory circuits (inhibitors of signaling kinases, such as Akt, (protein kinase B) or phosphatases, such as Wip-1), or increasing proapoptotic signaling in cancer cells (inhibitors of antiapoptotic proteins, TRAIL (TNF-related apoptosis-inducing ligand) agonists etc.)(Figure 1). The gene discussed is TP53; the disease is cancer.