Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to acquisition of the lethal phenotype. Here, by integrating a p53R270H-dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer. p53R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates to phenotypic evolution of the cancer. We specifically focused on the p53R270H-dependent regulation of the tyrosine kinase receptor macrophage-stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53R270H-dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in acquisition of a lethal phenotype by fine-tuning the chromatin landscape.