Abstract PHA01: Modeling the tissue-specific oncogenesis of mutant RAS

Abstract

Abstract RAS mutations are highly prevalent in tumors, especially those of the lung, colon, skin, and pancreas. The tissues in which these tumors arise are enriched for specific RAS isoform and codon preferences. For example, mutations in KRAS are prevalent in lung, colon, and pancreas, while NRAS mutations are predominantly found in melanoma. Additionally, mutations in KRAS predominantly occur at codons 12 and NRAS mutations at codon 61. Independent of the RAS isoform, the mutated codon contributes to distinct biochemical differences, with codon 61 mutations largely viewed as more biochemically active than codon 12 mutations. Previous RAS-mutant genetically engineered mouse (GEM) models resembled the tissue specificity observed in patients. In the colon, expression of KrasG12D but not NrasG12D induced colonic hyperplasia. While in melanocytes, the expression of NrasQ61R, but not NrasG12D, led to melanoma development. Given these data, we developed RAS-mutant GEM models to identify the tissues susceptible to RAS mutations and the differences among these animal models. To achieve this, we generated four conditional knockin GEM models to directly compare Kras and Nras mutations in codons 12 and 61; G12D and Q61R. To robustly determine the effects of mutant expression across a wide range of tissues, we utilized the ubiquitous and temporally expressed Cre, Rosa26-CreERT2. Following the induction of recombination by tamoxifen treatment, we observed rapid mortality in Kras-mutant animals. KrasQ61R mice survived to a median of 13 days while KrasG12D mice survived to a median of 22 days post-tamoxifen. However, the Nras-mutant mice have extended survival. While ongoing, these survival data suggest tissues acutely sensitive to Kras-mutant expression can tolerate or are resistant to Nras-mutant expression. When comparing the two Kras conditional knockin GEM models, we found expression of KrasG12D and KrasQ61R drove hyperproliferation in both lung and colon tissues to varying degrees and different tissue types in the colon. For instance, we observe colonic hyperplasia in KrasG12D mice and polypoid hyperplasia in KrasQ61R mice. Interestingly, the hematopoietic cells were exquisitely sensitive to expression of KrasQ61R, and these animals rapidly developed acute myeloid leukemia leading to death. These data illustrate how the strength of the constitutive activation of RAS proteins drives differential tumorigenesis. We plan to further our understanding of the tissue-specific tumorigenesis of mutant-RAS proteins by comparing the Kras- and Nras-mutant GEM models. This abstract is also being presented as Poster A01. Citation Format: Amanda R. Moore, Lisa McGinnis, Shiva Malek. Modeling the tissue-specific oncogenesis of mutant RAS [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PHA01.