Abstract 2944: Altering RAS oncogenic activity defines unique oncogenic fates

RAS family oncogenes demonstrate a tropism of specific driver mutations towards different cancers and understanding the impact of individual RAS mutations on oncogenic activity, signaling, and tissue-specific cellular responses could inform on the origin of cancer as well as development of potential therapies. To genetically interrogate how each mutation could differentially alter RAS signaling output in vivo, we created a panel of mice whereby two very different oncogenic mutations, G12D and Q61R, were expressed from a Cre-inducible LSL-Kras allele encoded with native (nat) or common (com) codons to generate low or high levels of oncoprotein. We show that this panel leads to a stepwise increase in RAS activity (GTP loading) with comQ61R > comG12D > natQ61R > natG12D. Global activation of these alleles induced a restricted number of tumors, with increasing active Kras generally leading to a more severe disease and decreased survival. Histopathological analysis revealed that high oncogenic activity induces highly aggressive myeloproliferative disease while there is a shift to more solid tumors as the signaling is dampened. RNASeq revealed that low levels of active Kras induce transcriptional features of a plastic state while high levels have all the hallmarks of potent oncogenic activity and resultant oncogenic stress. Such findings are suggestive of potential unique vulnerabilities during tumor initiation driven by different RAS mutants that may find clinical utility in the treatment of early stage cancer to prevent recurrence. Citation Format: Ozgun Erdogan, Nicole L. Pershing, Christopher M. Counter. Altering RAS oncogenic activity defines unique oncogenic fates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2944.