Gene signatures that are predictive of the sensitivity of a cancer or tumor to an MDM2i or an antagonist of the MDM2-p53 interaction. Differentially expressed genes in the provided gene signatures serve as biomarkers assessing the sensitivity of cancer and tumor samples to treatment or therapy with an MDM2i. Also provided are methods of determining MDM2i sensitivity of different cancer and tumor types and subtypes, based on the expression of genes in the MDM2i sensitive gene signatures, and treating individuals with an MDM2i if their cancers are determined to be MDM2i-sensitive. TP53 gene and p53 protein status can be determined for the samples undergoing analysis for MDM2i sensitivity. Methods, platforms, kits, reagents, and compositions of the invention provide advantageous approaches and tools for personalized or individualized treatments of cancer patients whose cancers exhibit sensitivity to MDM2 inhibitors.
