Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Abstract

Targeting aberrant kinase activity in cancer relies on unmasking cellular inputs such as growth factors, nutrients, and metabolites that contribute to cancer initiation and progression 1 . While the transition metal copper (Cu) is an essential nutrient that is traditionally viewed as a static cofactor within enzyme active sites 2 , a newfound role for Cu as a modulator of kinase signaling is emerging 3, 4 . We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. Targeting autophagy machinery is a promising therapeutic strategy in cancers 5 , but is limited by the absence of potent inhibitors and the emergence of resistance. The growth and survival of lung tumors driven by KRAS G12D is diminished in the absence of Ctr1 , depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a new molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.