Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Abstract

Although lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B-4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (Kras(G12D)) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a Kras(G12D)/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer. Lung cancer: A strategy for sidestepping a menacing mutation A protein that fuels inflammation could offer a therapeutic target to allow clinicians to bypass a highly tumorigenic but hard-to-treat mutant protein found in many lung cancers. Researchers have long struggled to develop medicines that inhibit KRAS, a signaling protein that commonly acquires mutations that turn it into a potent driver of cancerous growth. As an alternative, researchers led by Jae-Hong Kim of Korea University, Seoul, set out to identify proteins that govern the tumorigenic inflammatory response initiated by KRAS. They showed that a protein called BLT2 is highly expressed in KRAS-mutant lung cancer cells, and appears to contribute strongly to KRAS-mediated inflammation and tumor growth in mouse models. BLT2 could thus offer a useful downstream target for blocking the impact of mutant KRAS without grappling with the challenges of directly inhibiting KRAS.