Abstract
KRAS is among the most commonly mutated oncogenes in human malignancies. Although the advent of sotorasib and adagrasib, has lifted the "undruggable" stigma of KRAS, the resistance to KRAS inhibitors quickly becomes a major issue. Here, we reported that aldehyde dehydrogenase 1 family member A1 (ALDH1A1), an enzyme in retinoic acid biosynthesis and redox balance, increases in response to KRAS inhibitors and confers resistance in a range of cancer types. KRAS inhibitors' efficacy is significantly improved in sensitive or drug-resistant cells, patient-derived organoids (PDO), and xenograft models by ALDH1A1 knockout, loss of enzyme function, or inhibitor. Furthermore, we discovered that ALDH1A1 suppresses the efficacy of KRAS inhibitors by counteracting ferroptosis. ALDH1A1 detoxicates deleterious aldehydes, boosts the synthesis of NADH and retinoic acid (RA), and improves RARA function. ALDH1A1 also activates the CREB1/GPX4 pathway, stimulates the production of lipid droplets in a pH-dependent manner, and subsequently prevents ferroptosis induced by KRAS inhibitors. Meanwhile, we established that GTF2I is dephosphorylated at S784 via ERK by KRAS inhibitors, which hinders its nuclear translocation and mediates ALDH1A1's upregulation in response to KRAS inhibitors. In summary, the results offer valuable insights into targeting ALDH1A1 to enhance the effectiveness of KRAS-targeted therapy through ferroptosis in cancer treatment.