In this study, we performed cell-based assays to examine the effect of SARS-CoV-2 on p53 activation in cancer cells and demonstrate that SARS-CoV-2 spike interrupts the MDM2-p53 interaction in cancer cells and alters p53 signaling in cancer cells upon chemotherapy including blunted activation of p53 targets involved in growth arrest and apoptosis. This evidence concerns the gene MDM2 and cancer.