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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. KrasG12D-independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Both KrasG12D-dependent and KrasG12D-independent tumors display a high level of genomic instability, and KrasG12D-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 KrasG12D 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. [ABSTRACT FROM AUTHOR]

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., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The mammary epithelium undergoes several rounds of extensive proliferation during the female reproductive cycle. Its expansion is a tightly regulated process, fueled by the mammary stem cells and these cells' unique property of self-renewal. Sufficient new cells have to be produced to maintain the integrity of a tissue, but excessive proliferation resulting in tumorigenesis needs to be prevented. Three well-known tumor suppressors, p53, p16 I NK 4a , and p19 A RF , have been connected to the limiting of stem cell self-renewal and proliferation. Here we investigate the roles of these three proteins in the regulation of self-renewal and proliferation of mammary epithelial cells. Using mammary epithelial-specific mouse models targeting Trp53 and Cdkn2a, the gene coding for p16 INK4a and p19 ARF , we demonstrate that p53, p16 I NK 4a , and p19 A RF do not play a significant role in the limitation of normal mammary epithelium self-renewal and proliferation, whereas in the presence of the inflammatory cytokine TNF-α, Trp53 -/- Cdkn2a -/- mammary basal cells exhibit amplified proliferation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)