Targeting ALDH1A1 to enhance the efficacy of KRAS-targeted therapy through ferroptosis.

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 delet

SUBMITTER: Bian Y 

PROVIDER: S-EPMC11465744 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature