Abstract 1619: Characterising the in vivo response of lung tumors to KrasG12C inhibition
Authors: Martins Carla P. , Bidar Abdel , Karrberg Lillevi , Porritt Michelle , Seeliger Frank , Whiteley Rebecca , Hanson Lyndsey , Hallengren Liselotte , Hardaker Elizabeth , Barry Simon , Maresca Maresca , Bohlooly Mohammad , Cosulich Sabina , Ross Sarah 
Published: September 2020

Kras is one of the most frequently mutated oncogenes in human cancer and for decades, was considered untargetable. Interest on mutant Kras targeting was re-invigorated by the recent development of RasG12C-specific covalent inhibitors, with multiple compounds entering clinical trials in recent months.

Kras mutations affect ~30% of lung adenocarcinomas, one of the deadliest cancers worldwide, and G12C mutations account for ~47% of these cases. This high prevalence, coupled to the scarcity of effective therapies for these patients, make lung adenocarcinoma an ideal disease segment for KrasG12C inhibitors. However, our understanding of the potential heterogeneity in mutant Kras signalling in lung tumors, or on their dependence on this pathway, remains limited. To help maximize efficacy in the clinic and overcome potential mechanisms of resistance to KrasG12C inhibition, we determined the extent of addiction of lung tumors to KrasG12C in vivo. KrasG12C-driven autochthonous lung tumor models that are also deficient for key tumor suppressors (e.g. p53) were generated using CRISPR/Cas9. Similarly to previously described genetically engineered mouse models (GEMMs) of Kras-driven lung tumors, KrasG12C GEMMs developed multiple, independently evolving lung tumors that progressed to adenocarcinoma, and which closely mimicked the histopathological features of the human disease.

Treatment of established lung tumors in vivo with a KrasG12C inhibitor resulted in a rapid therapeutic response, with all mice exhibiting a marked decrease in tumor burden one week after treatment. MRI-guided longitudinal analysis of tumor responses showed that all tumors regressed during treatment, albeit with different kinetics. After 3 weeks of continuous treatment, MRI revealed significant tumor burden in vehicle-treated mice (2.4-fold increase from baseline), while those treated with the KrasG12C inhibitor showed overtly tumor-free lungs (5-fold decrease relative to start of treatment). Nevertheless, histological analysis revealed the presence of small foci of residual disease in lungs treated with the KrasG12C inhibitor. These data indicate that tumor cells from these GEMMs display differential sensitivity to KrasG12C inhibition. We are currently determining the relevance of tumor intrinsic and extrinsic factors for the maintenance of residual disease following mutant Kras-inhibition. Our data demonstrate the potential of autochthonous GEMM models to identify mechanism of response and resistance to mutant Kras inhibition in a physiologically-relevant context.

Citation Format: Carla P. Martins, Abdel Bidar, Lillevi Karrberg, Michelle Porritt, Frank Seeliger, Rebecca Whiteley, Lyndsey Hanson, Liselotte Hallengren, Elizabeth Hardaker, Simon Barry, Maresca Maresca, Mohammad Bohlooly, Sabina Cosulich, Sarah Ross. Characterising the in vivo response of lung tumors to KrasG12C inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1619.