Cell Death and Disease

KRAS G12C inhibitors provide an important treatment option for patients with KRAS G12C-mutant lung cancer, but some tumors respond poorly from the outset. Alterations in KEAP1, a gene involved in cellular stress responses, are associated with reduced sensitivity to these drugs. Some KRAS G12C-mutant lung cancers are resistant to KRAS G12C inhibitors from the outset. Loss of KEAP1 increases expression of pyruvate carboxylase (PC), allowing cancer cells to maintain metabolites required for growth during treatment. Genetic deletion of PC restored sensitivity to sotorasib and enhanced tumor suppression in mouse models.