biostudies-literatureUnknown6(32)Li YPharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e. g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient's body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively inOncotarget32339-52https://www.ebi.ac.uk/biostudies/studies/S-EPMC4741697biostudies-literatureMdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors.PMC4741697Saini PLi YDobbelstein MSriraman AfalseMdm2 inhibition confers protection of p53-proficient cells from the cytotoxic effects of Wee1 inhibitors.Pharmacological inhibition of the cell cycle regulatory kinase Wee1 represents a promising strategy to eliminate cancer cells. Wee1 inhibitors cooperate with chemotherapeutics, e. g. nucleoside analogues, pushing malignant cells from S phase towards premature mitosis and death. However, considerable toxicities are observed in preclinical and clinical trials. A high proportion of tumor cells can be distinguished from all other cells of a patient's body by inactivating mutations in the tumor suppressor p53. Here we set out to develop an approach for the selective protection of p53-proficient cells against the cytotoxic effects of Wee1 inhibitors. We pretreated such cells with Nutlin-3a, a prototype inhibitor of the p53-antagonist Mdm2. The resulting transient cell cycle arrest effectively in2015-01-01T00:00:00Z2015 Oct2025-04-26T11:23:28.507Z2019-03-27T02:08:25ZS-EPMC47416972643116310.18632/oncotarget.5891