Abstract 6850: A new syngeneic lung cancer model with KRAS and LKB double mutations for evaluating the efficacy of combined KRAS mutation targeted therapy and immunotherapy

Abstract Background: Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer-related deaths globally. Genetically engineered mouse models are vital for replicating the genetic and histopathological characteristics of NSCLC, enabling precise manipulation of tumor suppressors and oncogenes. These models facilitate the development of autochthonous tumors within their natural tissue environment. Mutations in LKB1 and KRAS, which frequently co-occur, are associated with resistance to immune checkpoint inhibitors (ICIs) in NSCLC. However, challenges in detecting and quantifying spontaneous lung tumors in mouse models persist. Therefore, there is a critical need for preclinical models with intact immune systems that allow for effective detection and quantification of spontaneous lung cancers. Such models are essential for evaluating the efficacy of therapies targeting KRAS and LKB1 double-mutant NSCLC. Methods: We developed a novel mouse model (KLL mouse) on the C57BL/6 background, incorporating the KRAS(G12D) mutation, LKB1 deficiency, and firefly luciferase expression. Spontaneous lung cancer was initiated via intranasal delivery of an adeno-associated virus (AAV)-based Cre recombinase system. Tumor progression was monitored longitudinally using micro-CT imaging. From this model, we derived the 279# tumor cell line from spontaneous lung tumors in one mouse (279#). This cell line was used to establish both subcutaneous and orthotopic lung tumor models for therapeutic efficacy studies. Conclusion: We successfully established a comprehensive preclinical platform for studying NSCLC with KRAS and LKB1 dual mutations. This platform includes a spontaneous lung cancer mouse model, a derived KLL cell line, and associated subcutaneous and orthotopic tumor models. These resources provide valuable tools for investigating optimal treatment strategies for NSCLC, particularly the combination of targeted therapies and immunotherapies. Citation Format: Lei Ci, Derek Reznik, Kai Zhou, Minghui Sun, Yi Li, Qin Huang, Ruilin Sun. A new syngeneic lung cancer model with KRAS and LKB double mutations for evaluating the efficacy of combined KRAS mutation targeted therapy and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6850.