We start by describing the physiological mechanisms of p53-mediated DNA damage response (DDR), p53-immediate early gene 5 (IER5)-heat-shock factor 1 (HSF1) pathway, and p53-p21-nuclear factor erythroid 2-related factor 2 (NRF2) pathway, and then describe how these pathways can be exploited by cancer cells to evade radiotherapy and chemotherapy. This evidence concerns the gene IER5 and cancer.