Modeling the genetic heterogeneity of KRAS mutant lung adenocarcinomas for therapeutic discovery.

Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer. Oncogenic driver mutations in KRAS are found in 36% of lung ADC cases and with a lack of specific KRAS inhibitors, this subset presents a significant clinical challenge. There is therefore an urgency to identify actionable co-occurring mutations as an alternative therapeutic approach. One of the most critical stress-response pathways in mammals is mediated by the transcription factor Nuclear Factor Erythroid-2-Related Factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-Associated Protein 1 (KEAP1). Loss-of-function mutations in KEAP1 have been identified in 19% of ADC, and often co-occur with KRAS mutations, but appear to be largely mutually exclusive with TP53 mutations. To best model these genetic subgroups of KRAS mutant lung ADC, we generated genetically engineered mouse models (GEMMs) whereby oncogenic KrasG12D was expressed either in combination with loss of p53 (KP mice) or Keap1 (KK mice). Critically, loss of Keap1 promoted KrasG12D-induced malignant transformation, which was associated with a unique metabolic program that could be exploited using pharmacologic inhibitors. Furthermore, bronchiolar epithelial cells appeared to be more sensitive than alveolar epithelial cells to transformation following Keap1 loss. Interestingly, this cell-type bias appeared to directly modulate the immune phenotype of lung tumors. Taken together, we have generated powerful in vivo models that enable us to address the relationship between tumor cells and resident immune cells to evaluate novel treatment strategies aimed at improving the long-term outcomes for patients carrying KRAS alterations. This abstract is also being presented as Poster B10. Citation Format: Sarah A. Best, Sheryl Ding, Boris Reljic, Ji-Ying Song, Kate D. Sutherland. Modeling the genetic heterogeneity of KRAS mutant lung adenocarcinomas for therapeutic discovery [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr PR03.