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

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the <i>CHUK</i> locus, which encodes IKKα, in human lung ADCs. The <i>CHUK</i> deletions significantly reduced the survival time of patients with lung ADCs harboring <i>KRAS</i> mutations. In mice, lung-specific <i>Ikkα</i> ablation (<i>Ikkα</i>^<i>ΔLu</i> ) induces spontaneous ADCs and promotes Kras^G12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs Kras^G12D-mediated ADC development in <i>Ikkα</i>^<i>ΔLu</i> mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.