Abstract 2679: A promoting role for the epithelial MyD88/IRAK4/NF-kB signaling in K-ras mutant lung tumorigenesis

K-ras mutation is the most common oncogenic alterations associated with lung cancer development. Unfortunately, all attempts to develop therapies directly targeting K-ras have been failed thus far, clearly stating the need for new strategies targeting downstream effectors and/or cooperating pathways of K-ras to overcome lung cancer displaying such a molecular profile. Using a conditional K-ras mutated lung cancer mouse model, CC-LR (CCSPcre/LSL-K-rasG12D) we previously showed that K-ras mutated lung tumorigenesis is associated with lung inflammation due to activation of NF-κB pathway and increased expression of its downstream targets in the lung. Here we have shown that lack of NF-κB activity in the airway epithelium by selectively targeting IKKβ, which is required for NF-kB activation, significantly reduces lung tumor burden (3.4-fold) and changes the inflammatory cells and mediators in the bronchoalveolar lavage fluid (BALF) of CC-LR mice. Immunohistochemically staining of lung tissues with specific markers, Ki-67 and CD-31, demonstrated significantly lower tumor cell proliferation and angiogenesis in CC-LR mice with lack of epithelial NF-kB activity. To further dissect the role of NF-κB pathway in this process, CC-LR mice were crossed with MyD88f/f mice to develop a mouse with lack of MyD88 (an adaptor protein upstream to IKKβ) in the airway epithelial cells (CC-LR/MyD88Δ/Δ mice). As we had hypothesized, the resulting tumor numbers in the lungs were significantly lower (1.9-fold) in CC-LR mice with lack of MyD88 in the airway epithelial cells compared to control CC-LR mice. Tumor reduction in CC-LR-MyD88Δ/Δ mice was also associated with decreased tumor cell proliferation and angiogenesis compared to control CC-LR mice. Surprisingly, unlike to lack of epithelial NF-kB activity, absence of MyD88 in the airway epithelium did not change the BALF inflammatory cell component of CC-LR mice. We then targeted another upstream signaling molecule to NF-kB, IRAK4, which is down stream of MyD88 by crossing CC-LR mice to IRAK4 knock out mice. Similar to lack of MyD88, we found a significant reduction in lung tumor number (1.8-fold) with no changes in BALF inflammatory cell component in CC-LR mice with lack of IRAK4 compared to the control CC-LR mice. Taken these together, we conclude that there is an essential role for MyD88/IRAK4/NF-kB pathway activation in promotion of K-ras mutant lung cancer. Citation Format: Susana Castro, Soudabeh Daliri, Maria Miguelina De La