Abstract 2579: The tumor landscape is molded by quantitative and qualitative signaling differences between different oncogenic KRAS mutations

Abstract

Abstract Despite over 50 possible oncogenic RAS mutations, cancers tend to have a bias towards a specific subset, often unique to each cancer type. As RAS mutation occur early, if not being the first mutations, these mutation patterns ostensibly reflect the selection of specific RAS mutations in each tissue to initiate tumorigenesis. Different RAS mutations can affect the level of active oncprotein and/or the type of pathways activated thereof. To attempt to determine the contribution of these two forms of signaling on the process of RAS mutation patterns in cancer, we generated four conditional murine Kras alleles containing one of two distinct oncogenic mutations, G12D or Q61R, encoded by native rare or common codons to induce low or high protein expression, respectively. These four alleles were globally activated throughout the mouse, revealing different tissue susceptibilities to the oncogenic Kras alleles. We observed that hematolymphopoietic lesions were preferentially initiated by the level of active RAS, squamous tumor were preferentially induced by one mutation over the other, while pulmonary carcinomas are susceptible to both activity level and the mutation type of the Kras allele. To further explore the signaling responses to the oncogenic Kras allele, we performed RNAseq analysis at the moment of tumor initiation, revealing that each allele induced a unique cellular response, ranging from transcriptional features of a plastic state to high oncogenic signaling and a stress response. We thus suggest that distinct RAS mutations impart a unique quantitative or qualitative signaling response that are selected in a tissue-specific fashion to initiate tumorigenesis, which has implications for early detection, interception, and prevention. Citation Format: Ozgun Le Roux, Christopher M. Counter. The tumor landscape is molded by quantitative and qualitative signaling differences between different oncogenic KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2579.