In ~70% of patients with pancreatic ductal adenocarcinoma, the TP53 gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multicenter patient data and multi-omics, we report that the misp53^R273H/C mutant is associated with cell cycle progression and a basal-like state compared to the misp53^R248W/Q mutant. Loss of misp53^R273H/C decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53^R273H/C specifically regulated the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor reduced misp53^R273H/C mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53^R273H/C-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.