Abstract C116: Oncogenic Kras signaling shapes the tumor microenvironment in lung adenocarcinoma

Abstract

Abstract Despite advancements in targeted therapy and immunotherapy, lung cancer remains the leading cause of cancer-related deaths in both men and women worldwide, with an estimated 2.2 million deaths each year. At 85%, non-small cell lung cancer (NSCLC) is by far the most common subtype, comprising adenocarcinomas and lung squamous cell carcinoma. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) genes are common, with the worst overall survival in KRAS mutant adenocarcinoma patients. About 40% of lung tumors with KRAS mutations also harbor mutations in tumor protein p53 gene (TP53), a tumor suppressor gene. KrasG12C and KrasG12D are both prevalent mutations in lung cancer. Sotorasib, a KrasG12C inhibitor, was recently approved for treatment of NSCLC. However, only 37% of patients have an objective response to Sotorasib, with a median duration of just 11 months. The KrasG12D inhibitor MRTX1133 is entering clinical trials; elucidating the mechanism of action and potential resistance is imperative to design combination treatment approaches. While cell-intrinsic mechanisms of resistance in epithelial oncogenic KRASG12D (Kras*) are well studied, our group and others have shown that KRASG12D also extrinsically regulates the tumor microenvironment (TME) in pancreatic cancer. Whether and how this oncogene regulates the TME of lung cancer is less understood. To study the crosstalk between epithelial lung cells expressing oncogenic KRAS and the surrounding TME, we have established a triple transgenic murine model of Kras*-driven NSCLC, wherein both lung epithelial-specific expression of Kras* and expression of mutant TP53R172H (Tp53*) can be controlled in an inducible and reversible manner. Our preliminary data show that expression of Kras* drives tumor growth, while Kras* depletion results in regression, even in the presence of Tp53*. Here we interrogate how Kras* modulates the TME in lung adenocarcinomas. Harnessing scRNA sequencing, immunohistochemistry, and multiple biochemical approaches, we will provide insight into changes in stromal and immune contexture upon Kras* depletion in mice. Citation Format: Rachael Baliira, Emily Lasse Opsahl, Ivana Barravecchia, Marina Pasca di Magliano, Stefanie Galban. Oncogenic Kras signaling shapes the tumor microenvironment in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C116.