In vivo functional screens reveal KEAP1 loss as a driver of chemoresistance in small cell lung cancer
Menée à l'aide de lignées cellulaires et de modèles de xénogreffes de tumeurs du poumon à petites cellules provenant de patients, cette étude met en évidence un mécanisme par lequel des altérations génétiques de KEAP1 favorisent la chimiorésistance des cellules cancéreuses
Exquisitely chemosensitive initially, small cell lung cancer (SCLC) exhibits dismal outcomes owing to rapid transition to chemoresistance. Elucidating the genetic underpinnings has been challenging owing to limitations with cellular models. As SCLC patient-derived xenograft (PDX) models mimic therapeutic responses, we perform genetic screens in chemosensitive PDX models to identify drivers of chemoresistance. cDNA overexpression screens identify MYC, MYCN, and MYCL, while CRISPR deletion screens identify KEAP1 loss as driving chemoresistance. Deletion of KEAP1 switched a chemosensitive SCLC PDX model to become chemoresistant and resulted in sensitivity to inhibition of glutamine metabolism. Data from the IMpower133 clinical trial revealed ~6% of patients with extensive-stage SCLC exhibit KEAP1 genetic alterations, with activation of a KEAP1/NRF2 transcriptional signature associated with reduced survival upon chemotherapy treatment. While roles for KEAP1/NRF2 have been unappreciated in SCLC, our genetic screens revealed KEAP1 loss as a driver of chemoresistance, while patient genomic analyses demonstrate clinical importance. In vivo genetic screens and patient genomic data analyses reveal that KEAP1 pathway alterations drive chemoresistance in SCLC.
Science Advances , article en libre accès 2025