Abstract 5161: Molecular mechanisms of early-stage lung adenocarcinoma initiation

Abstract

Abstract Lung cancer initiation and progression driven by epidermal growth factor receptor (EGFR) mutation has been extensively studied in the past decade. Though many leaps have been made in the field in terms of treatment, early diagnosis screening is not widely available or well established. Meanwhile, EGFR mutation is a significant driver of tumorigenesis and drug resistance. This receptor is related to many downstream pathways that influence cancer metabolism and the ability of tumor cells to adapt to changes in the tumor microenvironment. Our study finds that cancer metabolism plays a prominent role in the progression of tumorigenesis in early-stage lung cancer. Kynurenine, a metabolite from the tryptophan pathway, was highly upregulated in early-stage, EGFR-mutation driven lung cancer by metabolomic analysis. The connection between EGFR mutation and the upregulation of kynurenine remains largely unknown. We hypothesize that kynurenine, based on our preliminary data and as a ligand of the aryl hydrocarbon receptor, may have a dual role in early tumorigenesis. We propose that kynurenine may be used by tumor cells to modulate their response to stress by triggering anti-apoptotic pathways. Additionally, kynurenine may be used as a signaling molecule in the tumor microenvironment to allow the early tumor cells to evade immune detection through the transformation of macrophages from M1 to M2. Currently, our data show that indoleamine 2,3- dioxygenase 1 (IDO1), the rate-limiting enzyme of the tryptophan-kynurenine pathway, is significantly upregulated in early-stage, EGFR-driven lung cancer murine models by RNA-seq analysis. This supports our idea that IDO1 could help to modulate the response to cellular stress and to regulate the immune response to favor tumor development. We hope that IDO1 could be a potential clinical target and a potential biomarker for the dysregulation of this pathway. Citation Format: Alice Rodriguez-Fuguet, Luis Silva, John Asara, Xiaoman Li, Susumu Kobayashi, Wen Cai Zhang. Molecular mechanisms of early-stage lung adenocarcinoma initiation. [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 5161.