Interleukin-1 receptor-associated kinase-1 is a therapeutic target for gastric cancer.

Abstract

Interleukin-1 receptor-associated kinase 1 (IRAK1), a pivotal mediator in innate immunity and inflammatory processes, exhibits constitutive activation across various cancers. Our study highlights the significant role of IRAK1 in gastric cancer progression. We observed elevated IRAK1 expression in both gastric cancer tissues and cells, which correlates with malignant phenotypes, including heightened proliferation, colony formation, and migratory capacity in normal gastric cells upon IRAK1 overexpression. Silencing IRAK1 genetically in gastric cancer cells effectively suppressed these oncogenic traits. Notably, we found that gastric cancer cells display marked sensitivity to IRAK1/4 inhibitor and pacritinib, the latter targeting JAK2 and IRAK1 specifically, over the pan-JAK inhibitor tofacitinib. In vivo experiments using a xenograft mouse model demonstrated the efficacy of pacritinib in arresting gastric cancer growth without eliciting significant systemic toxicity. Immunohistochemical analyses further confirmed pacritinib's ability to attenuate tumor progression by inhibiting IRAK1 activity. Collectively, our results underscore IRAK1 as a promising therapeutic target in gastric cancer. Furthermore, the pharmacological blockade of IRAK1 by pacritinib, an established drug for myelofibrosis and severe thrombocytopenia treatment, holds potential for repurposing in gastric cancer therapy.