Significance To date, therapies are lacking that efficiently target the Kirsten rat sarcoma ( KRAS ) oncogene, which is responsible for approximately a quarter of all lung cancer cases in the United States. This study provides genetic evidence that the insulin/insulin-like growth factor 1 (IGF1) signaling, which modulates cellular survival, growth, and metabolism, is required for KRAS -driven lung cancer initiation. It further identifies a metabolic vulnerability in tumors with loss of such signaling, that is, the dependence on autophagy (a self-eating process), and protein degradation, to compensate for decreased amino acid levels. Such vulnerability could be exploited therapeutically using available autophagy and protein degradation inhibitors, in combination with insulin receptor/IGF1 receptor inhibitors, in patients with KRAS -mutant lung cancer.