Mesenchymal tumor cells drive adaptive resistance of Trp53(−/−) breast tumor cells to inactivated mutant Kras

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 Kras(G12D) , develops breast tumors. Upon inactivation of Kras(G12D) , tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of Kras(G12D) expression and return. Kras(G12D) ‐independent tumor cells show a strong mesenchymal profile with active RAS‐RAF‐MEK‐ERK (MAPK/ERK) signaling. Both Kras(G12D) ‐dependent and Kras(G12D) ‐independent tumors display a high level of genomic instability, and Kras(G12D) ‐independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial‐mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic Kras(G12D) withdrawal in a novel Trp53(−/−) breast cancer mouse model. To achieve long‐lasting responses in the clinic to RAS‐fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.