As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D, develops breast tumors. Upon inactivation of KrasG12D, tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. KrasG12Dâindependent tumor cells show a strong mesenchymal profile with active RASâRAFâMEKâERK (MAPK/ERK) signaling. Both KrasG12Dâdependent and KrasG12Dâindependent tumors display a high level of genomic instability, and KrasG12Dâindependent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelialâmesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53â/â breast cancer mouse model. To achieve longâlasting responses in the clinic to RASâfueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.