Cytosolic DNA sensor AIM2 promotes KRAS‐driven lung cancer independent of inflammasomes

Abstract Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co‐operators of oncogenic KRAS in the lung remains ill‐defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent‐in‐melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS‐addicted lung adenocarcinoma (LAC). In genetically defined and experimentally induced (nicotine‐derived nitrosamine ketone; NNK) LAC mouse models harboring the Kras G12D driver mutation, AIM2 was highly upregulated compared with other cytosolic DNA sensors and inflammasome‐associated PRRs. Genetic ablation of AIM2 in Kras G12D and NNK‐induced LAC mouse models significantly reduced tumor growth, coincident with reduced cellular proliferation in the lung. Bone marrow chimeras suggest a requirement for AIM2 in Kras G12D ‐driven LAC in both hematopoietic (immune) and non‐hematopoietic (epithelial) cellular compartments, which is supported by upregulated AIM2 expression in immune and epithelial cells of mutant KRAS lung tissues. Notably, protection against LAC in AIM2‐deficient mice is associated with unaltered protein levels of mature Caspase‐1 and IL‐1β inflammasome effectors. Moreover, genetic ablation of the key inflammasome adapter, ASC, did not suppress Kras G12D ‐driven LAC. In support of these in vivo findings, AIM2, but not mature Caspase‐1, was upregulated in human LAC patient tumor biopsies. Collectively, our findings reveal that endogenous AIM2 plays a tumor‐promoting role, independent of inflammasomes, in mutant KRAS‐addicted LAC, and suggest innate immune DNA sensing may provide an avenue to explore new therapeutic strategies in lung cancer.