IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways

Significance Reactive oxygen species (ROS) can promote tumorigenesis or kill cancer cells. How different cancer-associated genetic alterations regulate ROS balance and outcome is of great importance for the design of rational cancer treatments, many of which affect ROS metabolism and sensing. Kras activation induces a ROS defense system and cell senescence, which counteract its oncogenic activity. KRAS -activating mutations are accompanied by IKKα loss mutations that result in elevated NOX2 but decreased expression of the NRF2 ROS defense system. Thus, IKKα ablation turns the antitumorigenic effect of Kras-induced ROS to a protumorigenic effect that enhances Kras-induced progression of lung adenocarcinoma (ADC). Restoration of IKKα activity or inhibition of the pathways activated on its loss may offer new opportunities for ADC treatment.